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July-dec 2012.pmdTissue Engineering : Future of Pediatric Endodontics Dr. George Kurian Panampally, MDS*, Dr. Vivek M. Patil, MDS**,Dr. Rehan Khan, MDS***, During the last 10–15 years, there has been a tremendous increase in our clinical “tools” (i.e. materials, instruments and medications) and knowledge from the trauma and tissue engineering fields that can be applied to regeneration of a functional pulp-dentin complex. Tissue engineering is a multidisciplinary approach that aims to regenerate functional tooth tissue structure based on the interplay of three basic key elements:Stem cells, morphogens and scaffolds. A number of recent clinical case reports have revealed the possibilities that many teeth that traditionally would be treated byapexification may be treated by apexogenesis. Pulpal regeneration after tooth injury is not easy to accomplish, because of the infected pulp requires tooth extraction or root canal therapy. Current treatment modalities offer high levels of success for many conditions; an ideal form of therapy might consist of regenerative approaches in which diseased or necrotic pulp tissues are removed and replaced with healthy pulp tissue to revitalize teeth. This review discusses fundamental concepts of stem cell biology and tissue engineering within the context of regenerative dentistry.
Keywords : Tissue engineering, pediatric endodontics, future of pedodontics (GTR, GBR) procedures and distraction osteogenesis,4 There is a high rate of success in retention the application of platelet rich plasma (PRP) for bone of teeth by endodontic therapy. However, many augmentation,5emdogain for periodontal tissue teeth are not restorable because of apical resorption, fracture, incompletely formed roots or carious destruction of coronal structures. A novel augmentation,7 and preclinical trials on the use of approach to restore tooth structure is based on fibroblast growth factor 2 (FGF2) for periodontal biology i.e. regenerative endodontic procedures by tissue regeneration.8,9 A counter argument to the the application of tissue engineering. T issue development of regenerative endodontic procedure engineering is an emerging multi disciplinary field is that although the replaced pulp has potential to that applies the principles of engineering and life revitalize the teeth, it may also become susceptible sciences for the development of biological to further pulp disease and may require retreatment.
substitutes that can restore, maintain, or improve Over the last two decades, tissue engineering has tissue function.1 Regenerative endodontic evolved from science fiction to science. Indeed, procedures can be defined as biologically based isolated clinical case reports are consistent with the procedures, designed to predictably replace concept that certain clinical treatments might evolve damaged, diseased, or missing structures, including into regenerative endodontic procedures.10 dentin and root structures as well as cells of the pulp However, additional translational research is needed dentin complex with live viable tissues preferably to develop predictable clinical regenerative of the same origin that restore the normal procedures. The purpose of this article is to review physiologic functions of the pulp dentin complex.2 the biological principles of tissue engineering and Hermann (1952)3 was the first to carry out the hurdles that must be overcome to develop regenerative endodontic procedure, when he applied calcium hydroxide in vital pulp amputation.
Subsequent regenerative dental procedures The field of tissue engineering has literally included guided tissue or guided bone regeneration exploded during the last decade, and extensive Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012 reviews on dental applications are available for the to injury by induction of reparative dentinogenesis interested reader.2,11Here we briefly review 3 major suggests that a small population of competent components of tissue engineering from the concept progenitor pulp stem cells may exist within the of developing regenerative endodontic treatment Tissue engineering is the field of functional these cells are able to detect and respond to tooth restoration of tissue structure and physiology for injury is a scarce, but this information will be impaired or damaged tissues because of cancer, valuable for use in developing tissue engineering diseases, and trauma. The key elements of tissue engineering are stem cells, morphogens, and a Several, if not all, adult tissues have a subpopulation of stem cells. Examples of such tissues are the bone marrow, brain, skin, muscle, All tissues originate from stem cells. A stem cell is and adipose tissue.16,17 Stem cells have also been defined as a cell that has the ability to continuously found in several dental tissues. One of the first divide to either replicate itself (self replication) or tooth-related stem cell types was found in the pulp produce specialized cells that can differentiate into of permanent teeth and was named dental pulp stem various other types of cells or tissues.14 cells(DPSCs).18 In addition, stem cells from human exfoliated deciduous teeth (SHED), stem cells from the apical papilla, dental follicle progenitor cells, and periodontal ligament stem cells have also been characterized. Mechanistic studies focused on these cells are certainly improving our understanding of tooth development. In addition, this knowledge has The plasticity of stem cell defines its ability been applied in translational studies that aim at the to produce cells of different tissues. Stem cells are use of these stem cells in clinical settings where the commonly subdivided into totipotent, pluripotent regeneration of dental and craniofacial tissues is and multipotent categories according to their To accomplish endodontic regeneration, the applications depends on their proliferation rate, most promising cells are autologous postnatal stem differentiation potential, and accessibility. For cells, because these appear to have the minimum example, when bone marrow stem cells were disadvantages. Postnatal stem cells have been found compared with DPSCs, DPSCs presented favourable in almost all body tissues, including dental tissues.
results with regard to odontogenic capability.20 Stem Four types of human dental stem cells have been cells of dental origin can certainly generate dentaltissues. It has been shown that SHED and DPSCs are capable of generating a tissue that has (b). Stem cells from Human exfoliated deciduous morphological and functional characteristics that closely resemble those of human dental pulp.21 (c). Stem cells from apical papillae (SCAP) Other studies have expanded the potential of these (d). Periodontal ligament stem cells (PDLSCs) cells in the treatment of diseases and conditions such as muscular dystrophies, critical size bone differentiated cells which cannot proliferate to defects, corneal alterations, spinal cord injury, and replace subjacent irreversibly injured odontoblasts.
systemic lupus erythematosus. Such studies clearly The ability of both young and old teeth to respond demonstrate the plasticity and the differentiation Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012 potential of stem cells of dental origin. And finally, differentiation toward specific cell fates and to SHED cells have the unique advantage of being coordinate cellular processes that result ultimately retrievable from naturally exfoliated teeth, which in the generation of a new tissue or organ via tissue can be considered a “disposable” source of postnatal engineering-based approaches. More specifically, human tissue. Collectively, these studies suggest there are many similarities between morphogenic that the tooth constitutes an attractive source of factors regulating dentinogenesis and the factors stem cells that can potentially be useful in a wide that regulate reparative dentinogenesis.It can be easy to conclude that the field of dental tissue Recent evidence suggests that stem cells are engineering can benefit tremendously from studies localized in areas with low oxygen tension. Work on focused on the cellular and molecular mechanisms hematopoietic and neural stem cells showed that of odontogenesis. Growth factors have an important culturing progenitors in hypoxic conditions increases role in signalling reparative processes in dentin and the number of multipotent clones when compared pulp. Indeed, it is known that factors such as with normoxic cultures. In addition to effects on transforming growth factor, bone morphogenic differentiation and cell fate, hypoxia promotes proteins (BMPs), platelet-derived growth factor, survival and increases the proliferation of multipotent precursors. This phenomenon may endothelialgrowth factor (VEGF) are incorporated depict clinical situations in which pulp tissues are into thedentin matrix during dentinogenesis and are affected by noxious stimuli such as mechanical pulp retained thereas “fossilized” molecules.
exposure or trauma that leads to localized ischemia.
Interestingly, when these moleculesare released The secondary dentin bridge that formed under the from the dentin, they are bioactive andfully capable injury site is possibly the product of differentiated of inducing cellular responses, as for examplethose progenitors from deciduous pulp stem cell reservoir.
that lead to the generation of tertiary dentin and Further studies are required to understand whether DPSCs react differently to signalling molecules after hypoxic treatment, which might alter their insulin like growth factor-1 together with collagen has been found to induce complete dentin bridging Signalling molecules and dental pulp stem and tubular dentin format.24This indicates the potential of adding growth factors before pulp Growth factors and morphogenic factors are capping or incorporating them into restorative and proteins that bind to specific membrane receptors endodontic materials to stimulate dentin and pulp and trigger a series of signalling pathways that regeneration. The therapeutic effect of calcium coordinate all cellular functions. These molecules hydroxide may be because of its extraction of growth play a critical role during development, guiding factors from dentin matrix.25Once released, these processes that determine the fate of stem cells and growth factors may play key roles in signalling many regulate the generation of all tissues and organs in of the events of tertiary dentinogenesis, a response morphogenic molecules play a critical role in FGF2 plays a role not only as a differentiation physiological processes of tissue regeneration as, inducing factor in the injury repairprocess of pulpal for example, wound healing in the skin or dental tissue but also as a positive regulator of chemokine pulp responses to the progression of dentinal caries.
expression, which may help in tissue engineering The same growth factors that guide embryogenesis and pulp regeneration using Human DPSCs.
and physiological tissue regeneration can also be However, the fate of odotoblastic or osteoblastic differentiation, effective local delivery for FGF2 Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012 interaction of chemotactic and odontogenic factor 1. Root canal revascularization via blood clotting limitations need to be overcome.26 Ability of MTA to induce useful cellular response to achieve suitable tissue wound healing is by promoting by adhesion, supporting cellular proliferation and by inducing migration of human mesenchymal stem cells.
Mesenchymal stem cells are usually involved in tissue and bone remodelling, and local environment A study has found that inducing bleeding of pulp is thought to play an important role in the was easier and effective when an anestheticsolution commitment and differentiation of mesenchymal Collectively, there has been a tremendous increase in our clinical tools (i.e. materials, instruments, and medications) and knowledge from the trauma and environments for cell growth and differentiation, tissue engineering fields during the last decade.
promoting cell adhesion and migration. The scaffold Despite the impressive progress in tissue serves as a carrier for morphogens in protein therapy engineering approaches to regenerative pulp associated broad spectrum of responses in pulp (a). Biological or Natural e.g. Collagen, includes neural and vascular regeneration.15, 19, 28 (b). Artificial or Synthetic e.g. Poly lactic acid (PLA) Dental pulp is richly innervated. The main nerve Poly glycolic acid (PGA), Poly ethylene glycol (PEG), supply enters the pulp through apical foramen along Arginine, Hydroxyapatite, Tricalcium Phoshate.15 with the vascular elements. They include both sensory and sympathetic nerves. Pulpal nerves play New techniques involving viral or non viral vectors a key role in regulation of blood flow, dentinal fluid that can deliver genes for growth factors, flow, and pressure. The innervation of the pulp has morphogens, transcription factors and extracellular a critical role in the homeostasis of the dental pulp.
matrix molecules into target cell populations has The pulpal nerve fibers contribute to angiogenesis, been developed. The use of gene delivery in extravasation of immune cells and regulate endodontics would be to deliver mineralizing genes inflammation to minimize initial damage, maintain into pulp tissues to promote tissue mineralization.
pulp tissue, and strengthen pulpal defense Dr.Rutherford transfected ferret pulps with cDNA- mechanisms. The increasing interest in tissue transfected mouse BMP-7 that failed to produce a engineering of tooth must take into account neuro- reparative response, suggesting that further research pulpal interactions and nerve regeneration.31 is needed to optimize the potential of pulp gene therapy. Because of the apparent high risk of health Pulp vasculature plays an important role in hazards, the development of a gene therapy to regulating inflammation and subsequent repair and accomplish endodontic treatment seems very regeneration of dentin. There is an intimate association of the neural elements with vascular supply of the dental pulp suggesting the interplay of neural and vascular elements and involvement in Following are the areas of research that might have pulp homeostasis. The vascular endothelial growth application in the development of regenerative factor (VEGF) is an excellent regulator of Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012 angiogenesis and is known to increase vascular endodontic tissue engineering a reality in the near future. Progress will depend on the collaboration proliferation and differentiation of human dental between clinicians and researchers from diverse pulp cells. The utility of gene therapy in stimulation fields (e.g., biomaterials, stem cell biology and of vascular growth permits local stimulation of endodontics) working together toward the goal of developing biological approaches to regenerate The recent advances in vascular biology and VEGF and techniques of gene transfer and gene therapy will be of potential clinical utility in dentistry, Langer R, Vacnati JP: Tissue engineering.
especially in endodontics. Statin, 3-hydroxy-3-methy glutayl coenzyme A reductaseinhibitor is known to Murray PE, Garcia-Godoy F, Hargreaves KM: Pulp tissue contains a large amount of blood vessels current status and a call for action. Journal and peripheral nerves. Statin is known to induce angiogenesis and to regulate the survival and increase neurogenesis of neuronal cells, indicating pulp to vital amputation and calxyl capping.
the possible effectiveness of statin in pulp regeneration along with dentin regeneration.
Furthermore, statin has an anti-inflammatory effect Block MA, Cervini D, Chang A, Gottsegen GV: in various tissues. This could help to restore the Anterior maxillary advancement using tooth inflamed pulp tissue. Taken together, results suggest supported distraction osteogensis. Journal that statin might be an ideal active ingredient in pulp capping material to accelerate reparative dentin formation. However, at the same time attention has Kassolis JD, Rosen PS, Reynolds MA: Alveloar to be paid to the cell death observed in the cells treated with high concentration of statin. Therefore, a careful evaluation of the suitable concentration is freeze dried bone allograft: case series.
required before its use in pulp regeneration.33 Journal of Periodontology, 2000;71(10):1654- (c) To measure appropriate clinical outcomes we HeijlL ,Heden G , Svardstrom G , Ostgren A: Enamel matrix derivative (EMDOGAIN) in the treatment of infrabony periodontal defects.
Fjuimura K, Bessho K, Kusunoto K, Ogawa Y, Tissue engineering using the triad of dental pulp stem cells, morphogens and scaffolds may provide an innovative and biologically based atelopeptide type I collagen as a carrier for approach for generation of clinical materials and treatment of dental diseases. The challenges of introducing endodontic tissue engineered therapies are substantial; the potential benefits to patients and the profession are ground breaking.
Better understanding of cell interactions and growth along with further research can make Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012 21. Cordeiro MM, Dong Z, Kaneko T, Zhang Z, Miyazawa M, Shi S, Smith AJ, Nör JE. Dental Lin L, Chen MYH ,Ricucci D, Rosenberg PA: pulp tissue engineering with stem cells from 22. Sakdee JB, White RR, Pagonis TC, Hauschka 10. Banchs F, Trope M. Revascularization of 23. Smith AJ, Lesot H. Induction and regulation 11. Nakashima M, Akamine A. The application of crown dentinogenesis: embryonic events of tissue engineering to regeneration of pulp as a template for dental tissue repair? Crit 24. Lovschall H, Fejerskov O, Flyvbjerg A: Pulp- 12. Reddi AH. Role of morphogenetic proteins capping with recombinant human insulin like growth factor I (rhIGF-I) in rat molars.
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stromal stem cells versus dental pulp stem 31. Nosrat IV, Smith CA, Mullally P, Olson I, Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012 neurons and differentiate into neurons in vitro: implication for tissue engineering and Journal of Neurosciences, 2004;19(9):2388- 32. Matsushita K, Motani R, Sakuta T, Yamaguchi N, Koga T, Matsuo K, Nagaoka S, Abeyama K, Maruyama I, Torii M: The role of vascular endothelial growth factor in human dental activation of the AP-1 dependent signaling Fujisawa T, Oshima M, Tsuchimoto Y, Matsuka Y, Yasuda T, Shi S, Kuboki T: Simvastatin induces the odontogenic differentiation of human dental pulp stem cells in vitro and in vivo. Journal of Endodontics, 2009;35(3):367- *Reader, **Reader, *** Sr. Lect., ****Sr. Lect.
Dept. of Pedodontics & Preventive Dentistry Saraswati Dhanwantari Dental College & Hospital Saraswati Dhanwantari Dental College & Hospital Journal of Interdisciplinary Dental Sciences, Vol. 1, No. 2 July-Dec. 2012
ASSIGNMENT 2 for Marianna Marra The dataset ear.dat is based on 214 children with acute otitis media (OME) who participated in a randomized clinical trial (Mandel et.al., 1982,Pedriatic Infectious Diseases, 1, 310-316). Each child had OME at the beginning of the study in either one (unilateral cases) or both (bilateral cases) ears. Each child was randomly assigned to receive a 14-days cours