Scaff Olds For Dental Pulp Tissue Regeneration: A Review
International Dental & Medical Journal of Advanced Research (2016), 2, 1–12REVIEW ARTICLEScaffolds for dental pulp tissue regeneration: A reviewSaaid Ayesh Alshehadat1, Htun Aung Thu2, Suzina Sheikh Abdul Hamid3, Asma Abdullah Nurul4,Samsudin Abdul Rani5, Azlina Ahmad61Department of Conservative Dentistry, 2Department of Pediatric Dentistry, 6Department of Molecular Biology, School of Dental Sciences, UniversitiSains Malaysia, Kubang Kerian, Kelantan, Malaysia, 3Department of Tissue Bank, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian,Kelantan, Malaysia, 4Department of Biomedicine, School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia, 5Departmentof Oral & Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, United Arab EmiratesKeywordsDental pulp regeneration, dental tissueengineering, regenerative endodontics,scaffoldsCorrespondenceDr. Saaid Ayesh Alshehadat, School of DentalSciences, Universiti Sains Malaysia, KubangKerian, Kelantan, Malaysia. Tel: 609-767 1184.Fax: 609-767 5505. Email: saaid@usm.my/saaid1@hotmail.comReceived 13 December 2015;Accepted 14 January 2016AbstractA key of success in tissue regeneration is the use of a suitable scaffold either to carryspecialized cells ex vivo or to orchestrate and differentiate the homing of endogenouscells in vivo. This review aims to elucidate the materials that have been studied for dentalpulp tissue regeneration/engineering and summarize their properties, advantages, anddisadvantages. PubMed databases were searched for engineering, pulp regeneration,endodontics, and stem cells) without time restrictions. The search was restrictedto articles published in English language. When necessary, additional searches forthe structure, properties and history of the specific scaffold materials were achieved.Data from clinical, in vivo and in vitro studies were extracted, classified and reviewed.By providing an overview of possible scaffolds for pulp tissue regeneration, we aim toimprove the understanding of the requirements of the clinical application of regenerativeendodontics.doi: 10.15713/ins.idmjar.36IntroductionPulp tissue regeneration may present an ideal alternativetreatment to traditional root canal therapy. The present conceptof pulp tissue regeneration includes two possible approaches.[1]The first is revascularization, where a new pulp tissue is expectedto grow into the root canals from the remaining tissues existapically in the root canal.[2] The second includes the replacementof the diseased pulp with a healthy tissue that is able to revitalizethe tooth and restore dentin formation process. The stem celltherapy, gene therapy, three-dimensional (3D) cell printing,scaffold implantation, and pulp implantation are suggested forthis approach.[3]In tissue engineering, the selection of a suitable scaffold iscritical. Scaffolds can be identified as biocompatible structuresthat support cells growth and provide a suitable environment fortissue formation. Good scaffolds should allow cell attachment,proliferation, migration, differentiation, and provide mechanicalsupport for the extracellular matrix generation.[4,5] Ideally,scaffolds must be biodegradable as a native tissue and shoulddegrade in a controlled manner which is consistent with theformation of the new tissue.[6,7] Conductivity, suitable porosity,International Dental & Medical Journal of Advanced Research Vol. 2 2016sterilizability, and economic cost are other properties to beconsidered for scaffolds.[8,9]Scaffolds can be classified as artificial (synthetic) or natural.Natural scaffolds are usually more biocompatible and have theadvantage of providing specific cell interactions.[10] However,they have the shortcomings of difficulty in obtaining in largeamounts, the large batch to batch variations, limited designability and the lack of good mechanical properties. In contrast,synthetic-derived scaffolds have good reproducible mechanicalproperties and controlled degradation time, but they lack thepresence of cellular signals required for tissue engineering.[10]Scaffold for Pulp Tissue RegenerationScaffold for revascularization of immature permanent teethRoot canal revascularization procedure aims to restore the bloodsupply of necrotic pulp tissues of permanent immature teeth.[2]Some researchers indicate revascularization as a regenerativeapproaches[3] others considered pulp regeneration is incompleteif restricted only to revascularization and should includeother significant events such as alignment of odontoblasts on1
Scaffolds for pulp regenerationAlshehadat, et al.the dentin surface, and generation of the different types ofdental pulp nerve fibers (i.e., nociceptive, sympathetic, andparasympathetic)[11] The revascularization technique dependson the induction of bleeding through the open apical foramenintra the chemically cleaned canal. The canal dentin and theblood clot[2] provide scaffolds in the root canal revascularization.More recently, platelet-rich plasma (PRP) and platelet-richfibrin (PRF) are suggested as further possible scaffolds.[12]Table 1 shows materials used for dental pulp revascularizationby different researchers.Blood clotThe utilization of a blood clot to regenerate dental pulptissues was first practiced by Ostby and resulted in a growth ofgranulation tissues, fibrous tissues or cementum-like tissues intothe root canals.[13] In 1974, Myers and Fountain[14] succeeded togenerate 0.1-1.0 mm of soft connective tissues into the root canalusing blood clots. Later on, successful clinical landmark casesof pulp tissue revascularization were reported.[2,15] Currently,there are growing shreds of evidence of the success of bloodclot revascularization procedure for pulp tissue regeneration inimmature teeth. Since it is believed that tissues are not able togrow into empty spaces with the absence of suitable scaffolds,[16]it can be suggested that blood clots yield good scaffolds to fillintracanal spaces and aid the growth of new tissues.[17]The blood clot consists of fibrin matrix that traps cellsnecessary for tissue regeneration.[1] It also provides a suitablepathway for cells from the periapical area including macrophagesand fibroblasts to migrate into the root canal and enhance thenew tissue growth.[17,18] The rich content of growth factors allowsthe blood clot to play an important role in cell differentiation[18,19]and thus, promotion of tissue regeneration.[20] These growthfactors include platelet-derived growth factor (PDGF), vascularendothelial growth factor (VEGF), and platelet-derived epithelialgrowth factor, known also as vascular permeability factor.[21,22]The limitation of the blood clot as a scaffold for pulpregeneration comes from the fact that the composition of a clotis variable. The concentrations of cells trapped in a clot mightdiffer leading to unpredictable outcomes. Therefore, usingPRP as a controlled scaffold to replace the blood clot in tissueregeneration was suggested.[12,23,24]PRP and PRFThe PRP was introduced to dentistry world in 1997 byWhitman.[25] Since then it was widely used to promote woundhealing after oral maxillofacial, implant, and endodonticsurgery.[23,25-29] Because it is rich with important growthfactors, PRP has been nominated as a scaffold for pulp tissueregeneration.[12,30,31] The revascularization of pulp-like tissue innecrotic immature teeth using PRP was reported.[32,33] It wassuggested that PRP is able to attract stem cells from surroundingperiapical tissues.[12] When PRP is combined with dental pulpcells, increased vital tissue regeneration was observed in rootcanals of dogs’ immature teeth.[34]Some of the growth factors and cytokines found in plateletsare transforming growth factor-β (TGF-β) 1 and 2, PDGF,VEGF, epidermal growth factor, fibroblast growth factor,insulin-like growth factor-2 (IGF-2), IGF-1, keratinocytegrowth factor, interleukin-8, and connective tissue growthfactor.[35,36] These factors have the ability to enhance woundhealing and stimulate matrix remodeling and angiogenesis.[37]In addition, they have a role in controlling local inflammatoryresponse and promoting cell proliferation and differentiationduring osteogenesis.[38]To prepare PRP, blood is extracted, collected withanticoagulant and immediately centrifuged for a variable timewhich is completed within an hour. By first centrifugationprocess, blood is separated into three layers, the bottom is redblood cells, the second is a buffy coat layer and the supernatantlayer which is acellular plasma known as platelet-poor plasma.Table 1: Materials used for dental pulp revascularization by different researchersMaterialsBlood clotResearcherOstby, 1961[13]ResultsGrowth of granulation tissues, fibrous tissues or cementum-like tissues into the root canalsMyers and Fountain, 1974[14][2]Banchs and Trope, 2004[15]Generation of soft connective tissues into the root canalSuccessful revascularization of immature permanent teeth with apical periodontitisIwaya et al., 2001Successful revascularization of an immature permanent tooth with apical periodontitisand sinus tractThibodeau and Trope, 2007[17]Successful pulp revascularization of a necrotic infected immature permanent toothassociated with swellingDing et al., 2009[31]Exhibit complete root development, with a positive response to pulp testingPlatelet-rich plasma Torabinejad and Turman, 2011[12] Regeneration of vital tissues in a tooth with necrotic pulp and a periapical lesionPlatelet-rich fibrin2Bezgin et al., 2014[32]Concentrated PRP resulted in narrowing of the apical foramen and convergence of theapical walls in the treated teethJadhav et al., 2015[33]Periapical healing, apical closure, root lengthening and dentinal wall thickeningRevascularization of an immature, non-vital permanent tooth with apical periodontitisFakhr Tabatabayi et al., 2015[43]Resolution of periapical lesion, root development and apical closure of necrotic immaturetoothInternational Dental & Medical Journal of Advanced Research Vol. 2 2016
Alshehadat, et al.The following steps differ between protocols but always aim tocollect the buffy coat layer and discard the other layers.Clinically, the ability of PRP to create vital tissue in the rootcanal is relatively faster.[12] PRP clots into the root canal within5 min.[12] It is faster than blood which needs about 15 min toclot.[2,17] In addition, PRP is easier to apply, harder, and moresuitable for the subsequent placement of mineral trioxideaggregate and permanent restorations.[12] Unlike blood clotprocedure, anesthesia is not necessary for PRP applicationsince periapical bleeding is not indicated. PRP has an additionalvalue in patients where bleeding into root canal cannot beestablished.[31] However, blood extraction from young patientsand the need of additional equipment are the main disadvantagesof PRP procedure.Currently, PRP is referred as a first-generation plateletconcentrate, and the PRF is known as a second-generationplatelet concentrate.[39] PRF was developed first by Choukrounet al. (2001)[39] It has the benefit of slow release of growth factorsfor a prolonged period of 7-14 days. Hence, it is superior to PRPwhich shows fast release growth factors in 7-14 h.[40] Successfulpulp revitalization cases using PRF were reported.[41-43]DentinThe root canal space is wholly enclosed by acellular dentinmatrix rich with growth factors.[44,45] Some of them are Growthhormone,[46] IGF-1 and -2,[47-49] bone morphogenetic protein-2(BMP-2), -4 and -6,[50] and TGF-β-1, -2 and -3.[45,51,52] Whenrelease from dentin matrix, these growth factors play a keyrole in regulation the inflammatory response, tissue healingand regeneration and odontoblast differentiation.[45,47,53] Therelease of growth factors can be enhanced if dentin is treatedwith chelating agents such as an ethylene diamine tetraaceticacid (EDTA). Although it was reported that removal of thewhole smear layer from the root canal walls is with a less valuefor cell attachment,[54] it is believed that dentin treated withEDTA releases some growth factors necessary to stimulatedentin regeneration such as TGF-β.[45,55] EDTA-treated dentinwas able to induce the regeneration of complete dentin tissuesin vivo.[45,56]Scaffolds for pulp regenerationsimple hydrolysis.[66] Table 3 shows some synthetic polymersused previously for dental pulp regeneration.The first clinical use of PGA was as an absorbable suture.[67]It was also used in head and neck surgery as an implant for boneregeneration, cartilage repair,[68] cartilage reconstruction,[69]and as a potential membrane for periodontal therapy.[70] PGAis considered an immunologically inert material althoughmigration of inflammatory monocytes were observed followingPGA implant.[71] No infection or reaction of a foreign bodywere observed following using PGA pins to fix displaced elbowfractures in children.[72]The first attempt for pulp tissue engineering in vitro wasachieved using PGA with human pulpal fibroblasts. A newtissue-like construct with similar cellularity as in normal pulptissue could be observed.[73] When compared to alginate anda Type I collagen hydrogel, PGA was more conducive for cellproliferation.[62] PGA scaffold enhanced the growth of new bloodvessels and the odontogenic differentiation of human fibroblastswhen cultured on it.[74] However, collagen sponge scaffold wasfound to be superior to PGA in vitro and in vivo for tooth-tissueengineering purposes using porcine dental pulp cells.[75]Similarly, the poly-L-lactic acid (PLLA) polymer is a widelyused, FDA-approved biodegradable polymer.[76,77] PLLAscaffold was able to produce tissue similar in architecture andcellularity to dental pulp tissue when transplanted with humandermal microvascular endothelial cells,[78] or stem cells in humanexfoliated deciduous teeth (SHED)[79] into immunodeficientTable 2: Possible scaffolds for dental pulp regenerationClassificationSynthetic polymersPLAPLLAPLGAOPLAPGA/PLLABioactive ceramicsBCPBGSilicate bioactive glassborate and borosilicate glassSynthetic polymersInternational Dental & Medical Journal of Advanced Research Vol. 2 2016HAβ-TCPPossible scaffolds for pulp tissue regeneration [Table 2]Synthetic biodegradable polymers, such as polyglycolic acid(PGA), polylactic acid (PLA) and poly-lactic-coglycolide, havebeen initially approved by the Food and Drug Administration(FDA) as drug delivery systems.[57,58] The application of thesepolymers as matrices for cell transplantation was the firstsuggested by Vacanti et al.[59] Their biocompatibility and abroad range of reproducibility make them attractive for tissueengineering studies.[60-63] Polymers scaffold shape, porosity,mechanical properties, pores diameter, and degradation timecan be successfully controlled in the preparation techniques.[64,65]Degradation of synthetic polymers are generally occurred byScaffoldPGANaturally derived scaffoldFibrinCollagenHYA spongeAmniotic membranePolysaccharides (chitin, chitosan,cellulose, alginate, agar, pectins,dextran and glycosaminoglycans)PGA: Polyglycolic acid, PLA: Poly-lactic acid, PLLA: Poly-L-lacticacid, PLGA: Poly-lactic-coglycolide, OPLA: Open-cell polylactic acid,HA: Hydroxyapatite, β-TCP: Beta-tricalcium phosphate, BCP: Biphasiccalcium phosphate, HYA: Hyaluronic acid, BG: Bioactive glass3
Scaffolds for pulp regenerationAlshehadat, et al.Table 3: Synthetic polymers used for dental pulp regeneration by different researchersScaffoldPGAResearcherMooney et al., 1996[73]ResultsA new tissue-like construct with similar cellularity as in normal pulp tissueBuurma et al., 1999[74]Growth of new blood vessels and odontogenic differentiation of human fibroblasts[62]Bohl et al., 1998PLLAGrowth of dental pulp-like tissues with a very high cell density and significant collagen depositionNör et al., 2001[78]Growth of tissue similar in architecture and cellularity to dental pulp tissue[79]Sakai et al., 2004Differentiate of stem cells seeded on PLLA into angiogenic endothelial cells and odontoblastscapable of generating tubular dentinOPLAGotlieb et al., 2008[82]Stem cells seeded on OPLA and transplanted into cleaned and shaped canals of human extractedteeth were able to attach to the root canal dentinPGA/PLLAYoung et al., 2002[80]Regeneration of a tooth crown contained enamel, dentin and a well-defined pulp chamber[81]Duailibi et al., 2008Engineering of tooth crowns, containing dentin, enamel, pulp, and periodontal ligament tissuesmice. A PGA/PLLA scaffold was also successful for theregeneration of a tooth crown contained enamel, dentin and awell-defined pulp chamber using cells isolated from tooth budsand transplanted into rat omentum.[80] When similar constructswere transplanted into rat jaws, periodontal ligament tissuescould be observed around the generated crown.[81] Finally, thesynthetic open-cell PLA (OPLA) is another promising polymerfor dental pulp regeneration. SHED seeded on OPLA andtransplanted into cleaned, and shaped canals of human extractedteeth were able to attach to the root canal dentin.[82]Bioactive ceramicsin the in vivo conditions after implantation.[97] However, to thebest of our knowledge, the advantages of the combination ofa polymer and a ceramic for pulp tissue regeneration have notbeen tested yet.Bioactive glass (BG)BG is a group of synthesized surface reactive biomaterials thathave an amorphous structure and high mechanical strength.[84] Ithas been investigated extensively for the use as implant materialsin the human body to repair and replace diseased or damagedbone. BG is able to support osteogenesis[98] and its ability tosupport pro-angiogenesis has been reported recently.[99] Thissuggests the application of BG in soft tissue repairing andengineering.[84] Silicate BG (known by its commercial name:Bioglass) has been traditionally used in BG researches.[100]However, for tissue engineering purposes, new BGs based onborate and borosilicate compositions have been suggested,[101-103]the biocompatibility and controllable degradation rate of thesenew glass scaffolds have been reported.[104,105] When degrades,BG will be converted into an HA-like substance that is able tobond to soft and hard tissues. The degradation also releasesions that contribute in osteogenesis and angiogenesis.[106,107] Itis well recognized that odontogenesis pathway is very similar toosteogenesis pathway and that odontogenesis and angiogenesisare essential for the successful generation of the dentin-pulpcomplex. Taken together, all these facts suggest that using BGas a scaffold for dentin and dental pulp engineering might bepromising.Calcium phosphate ceramics such as hydroxyapatite (HA), betatricalcium phosphate (β-TCP), and biphasic calcium phosphate(BCP) are totally biocompatible and bioactive crystallizedmaterials.[83,84] These bioactive ceramics were widely used asbone graft materials and showed a great ability to form a strongdirect bond with the host bone.[85] Cells cultured on the porousform of ceramics could attach, proliferate, and expressed dentinsialophosphoprotein, which is a dentin marker.[86]HA [(Ca10 (PO4)6(OH)2] has been suggested as aneffective scaffold for regeneration of dentin and dentin-pulpcomplex.[87-90] HA is a non-biodegradable ceramic whileβ-TCP [β-TCP Ca3(PO4)2] is considered a biodegradable.[91]However, the mechanical properties of TCP are inferior to thoseof HA. BCP has been developed from HA and TCP to displaythe advantages of the both ceramics.[92,93] BCP was widelyinvestigated as a possible scaffold for pulp and dentin tissueregeneration. When pulp-derived cells were mixed with HAor HA/TCP and transplanted subcutaneously in nude mice,bone and dentin-like mineralized tissues were generated.[92,94,95]Moreover, the formation of dentin bridge after pulp capping inpig teeth model was stimulated using pulp cells seeded on HA/TCP scaffold.[96]Another combination of a polymer [poly (D,L-lactide-coglycolide)] and a ceramic (β-TCP) was also tested.[97] The resultedscaffold showed excellent mechanical
More recently, platelet-rich plasma (PRP) and platelet-rich fi brin (PRF) are suggested as further possible scaff olds.[12] Table 1 shows materials used for dental pulp revascularization by diff erent researchers. Blood clot The utilization of a blood clot to regenerate dental pulp tissues was fi rst practiced by Ostby and resulted in a .
with calcium hydroxide was slower than that of MTA, both materials were successful for pulp capping in human teeth. (J Endod 2008;34:1-6) Key Words Biocompatibility, calcium hydroxide, human pulp, min-eral trioxide aggregate, pulp capping, pulp therapy T he aim of conservative pulp therapy is to maintain the coronal and radicular pulp
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fluffed using a domestic food processor (Sunbeam Oskar II). 30.0 g o.d of pulp was charged with different concentrations of ozone (Z) at 30.0% consistency to delignify the pulp. After the ozone treat-ment, the pulp was washed to neutral pH with deionised water. Bleaching: Pulp
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ELSEVIER Artificial Intelligence 82 ( 1996) 369-380 Book Review Stuart Russell and Peter Norvig, Artificial Intelligence Artijcial Intelligence: A Modem Approach * Nils J. Nilsson Robotics Laboratory, Department of Computer Science, Stanford University, Stanford, CA 94305, USA 1. Introductory remarks I am obliged to begin this review by confessing a conflict of interest: I founding director .
