Photochemical & Photobiological Sciences, 2021
Mesenchymal stem cells (MSCs) and photobiomodulation (PBM) both offer significant therapeutic pot... more Mesenchymal stem cells (MSCs) and photobiomodulation (PBM) both offer significant therapeutic potential in regenerative medicine. MSCs have the ability to self-renew and differentiate; giving rise to multiple cellular and tissue lineages that are utilised in repair and regeneration of damaged tissues. PBM utilises light energy delivered at a range of wavelengths to promote wound healing. The positive effects of light on MSC proliferation are well documented; and recently, several studies have determined the outcomes of PBM on mineralised tissue differentiation in MSC populations. As PBM effects are biphasic, it is important to understand the underlying cellular regulatory mechanisms, as well as, provide accurate details of the irradiation conditions, to optimise and standardise outcomes. This review article focuses on the use of red, near-infra-red (R/NIR) and blue wavelengths to promote the mineralisation potential of MSCs; and also reports on the possible molecular mechanisms whic...
Where a licence is displayed above, please note the terms and conditions of the licence govern yo... more Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Air-liquid interface (ALI) cultures are used to produce stratified epithelial tissues in vitro, n... more Air-liquid interface (ALI) cultures are used to produce stratified epithelial tissues in vitro, notably for the production of oral mucosal equivalents. Currently, there are few purpose-built devices, which aim to enhance the ease and reproducibility of generating such tissue. Most ALI cultures utilize stainless steel grids or cell culture inserts to elevate the matrix or scaffold to the surface of the culture media. In this study, a novel buoyant epithelial culture device (BECD) was designed to both contain a fibroblast-seeded collagen hydrogel and float in culture media, thereby automatically maintaining the ALI without further user intervention. BECDs aim to mitigate several issues associated with ALI culture; reducing the chance of media flooding the epithelial layer from physical disturbance, reducing technique sensitivity for less-experienced users, and improving the reproducibility of the epithelia generated. H400 oral squamous cell carcinoma cells cultured in BECDs for 7, 14, and 21 days showed continuous increase in epithelial tissue thickness with expected localization of epithelial differentiation markers: cytokeratin 5, involucrin, and E-cadherin. Fused filament fabrication three-dimensional printing with polypropylene used in BECD production allows for rapid turnover and design iteration, presenting a versatile, adaptable, and useful tool for application in in vitro cell culture.
Background Human dental pulp stem cells (hDPSCs) have received widespread attention in the fields... more Background Human dental pulp stem cells (hDPSCs) have received widespread attention in the fields of tissue engineering and regenerative medicine. Although amphiregulin (AREG) has been shown to play a vital function in the biological processes of various cell types, its effects on DPSCs remain largely unknown. The aim of this study was to explore the specific role of AREG as a biologically active factor in the regeneration of dental pulp tissue. Methods The growth of hDPSCs, together with their proliferation and apoptosis, in response to AREG was examined by CCK-8 assay and flow cytometry. We explored the effects of AREG on osteo/odontogenic differentiation in vitro and investigated the regeneration and mineralization of hDPSCs in response to AREG in vivo. The effects of AREG gain- and loss-of-function on DPSC differentiation were investigated following transfection using overexpression plasmids and shRNA, respectively. The involvement of the mitogen-activated protein kinase (MAPK) ...
Dental stem cells (DSCs) holds the ability to differentiate into numerous cell types. This proper... more Dental stem cells (DSCs) holds the ability to differentiate into numerous cell types. This property makes these cells particularly appropriate for therapeutic use in regenerative medicine. We report evidence that when DSCs undergo osteogenic differentiation, the osteoblast-like cells can be reverted back to a stem-like state and then further differentiated toward the osteogenic phenotype again, without gene manipulation. We have investigated two different MSCs types, both from dental tissues: dental follicle progenitor stem cells (DFPCs) and dental pulp stem cells (DPSCs). After osteogenic differentiation, both DFPCs and DPSCs can be reverted to a naïve stem cell-like status; importantly, dedifferentiated DSCs showed a greater potential to further differentiate toward the osteogenic phenotype. Our report aims to demonstrate for the first time that it is possible, under physiological conditions, to control the dedifferentiation of DSCs and that the rerouting of cell fate could potent...
The recent discovery of mesenchymal stem cells within periapical lesions (PL-MSC) has presented n... more The recent discovery of mesenchymal stem cells within periapical lesions (PL-MSC) has presented novel opportunities for managing periradicular diseases in adult teeth by way of enhancing tissue regeneration. This discovery coincides with the current paradigm shift toward biologically driven treatment strategies in endodontics, which have typically been reserved for non-vital immature permanent teeth. One such approach that shows promise is utilizing local endogenous non-collagenous dentine extracellular matrix components (dECM) to recruit and upregulate the intrinsic regenerative capacity of PL-MSCs in situ. At picogram levels, these morphogens have demonstrated tremendous ability to enhance the cellular activities in in vitro and in vivo animal studies that would otherwise be necessary for periradicular regeneration. Briefly, these include proliferation, viability, migration, differentiation, and mineralization. Therefore, topical application of dECMs during ortho-or retrograde root canal treatment could potentially enhance and sustain the regenerative mechanisms within diseased periapical tissues that are responsible for attaining favorable clinical and radiographic outcomes. This would provide many advantages when compared with conventional antimicrobial-only therapies for apical periodontitis (AP), which do not directly stimulate healing and have had stagnant success rates over the past five decades despite significant advances in operative techniques. The aim of this narrative review was to present the novel concept of exploiting endogenous dECMs as clinical tools for treating AP in mature permanent teeth. A large scope of literature was summarized to discuss the issues associated with conventional treatment modalities; current knowledge surrounding PL-MSCs; composition of the dECM; inductive potentials of dECM morphogens in other odontogenic stem cell niches; how treatment protocols can be adapted to take advantage of dECMs and PL-MSCs; and finally, the challenges currently impeding successful clinical translation alongside directions for future research.
Caries results in the demineralization and destruction of enamel and dentine, and as the disease ... more Caries results in the demineralization and destruction of enamel and dentine, and as the disease progresses, irreversible pulpitis can occur. Vital pulp therapy (VPT) is directed towards pulp preservation and the prevention of the progression of inflammation. The outcomes of VPT are not always predictable, and there is often a poor correlation between clinical signs and symptoms, and the events occurring at a molecular level. The inflamed pulp expresses increased levels of cytokines, including tumour necrosis factor (TNF)a, interleukin (IL)-1a, IL-1b, IL-4, IL-6, IL-8, IL-17 and IL-23, which recruit and drive a complex cellular immune response. Chronic inflammation and sustained cytokine release can result in irreversible pulp damage and a decreased capacity for tissue healing. Other chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases and rheumatoid arthritis, are also characterized by an dysregulated immune response composed of relatively high cytokine levels and increased numbers of immune cells along with microbial and hard-soft tissue destructive pathologies. Whilst anti-cytokine therapies have been successfully applied in the treatment of these diseases, this approach is yet to be attempted in cases of pulp inflammation. This review therefore focuses on the similarities in the aetiology between chronic inflammatory diseases and pulpitis, and explores how anticytokine therapies could be applied to manage an inflamed pulp and facilitate healing. Further proof-ofconcept studies and clinical trials are justified to determine the effectiveness of these treatments to enable more predictable outcomes in VPT.
Research over several decades has increased our understanding of the nature of reparative and reg... more Research over several decades has increased our understanding of the nature of reparative and regenerative processes in the dental pulp, at both the cellular and molecular level. However, advances in scientific knowledge have not translated into novel clinical treatment strategies for caries-induced pulpitis. This narrative review explores the evidence regarding the ability of inflamed pulp tissue to heal and how this knowledge may be used therapeutically. A literature search and evidence analysis covering basic, translational and clinical pulp biology research was performed. The review focuses on (1) the regenerative and defense capabilities of the pulp during caries-induced inflammation; (2) the potential of novel biomaterials to harness the reparative and regenerative functions of the inflamed pulp; and (3) future perspectives and opportunities for conservative management of the inflamed pulp. Current conservative management strategies for pulpitis are limited by a combination of...
Where a licence is displayed above, please note the terms and conditions of the licence govern yo... more Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Journal of Ege University School of Dentistry, 2020
Boron is a bioactive trace element found in humans and essential for the growth and maintenance o... more Boron is a bioactive trace element found in humans and essential for the growth and maintenance of bone and also has reported anti-inflammatory and antimicrobial activity. Boric acid is a well-characterised boron-containing compound which reportedly can reduce periodontal inflammation. Thus, the aim of the current study was to evaluate the possible bactericidal and/or bacteriostatic effects of boric acid on the periodontal pathogens: Fusobacterium nucleatum and Porphyromonas gingivalis. Materials and Methods: Minimum inhibitory concentration (MIC) of boric acid on F. nucleatum (ATCC 10953) and P. gingivalis (ATCC 33277) were determined by the broth microdilution method. Overnight cultures were diluted to the following starting concentrations: 5x10 5 cfu/ml for F. nucleatum and 5x10 6 cfu/ml for P. gingivalis. After incubation for 48h at 37°C in an anaerobic cabinet the absorbance of the cultures was measured. The minimum bactericidal concentration (MBC) was determined by plating an aliquot of the cell suspensions on agar plates, and bacteria were counted after incubation at 37°C for 48 h under anaerobic conditions. Results: Boric acid was able to inhibit the growth of F. nucleatum at a concentration of 780 nM and P. gingivalis at a concentration of 1.56 µM. The MBC of boric acid was 19 mM for F. nucleatum however using tested concentrations (75 mM-1nm) were insufficient to provide an MBC for P. gingivalis. Conclusion: Boric acid may be a possible candidate for providing local antimicrobial actions on periodontal pathogens and therefore may have potential as a therapeutic intervention in the management of periodontal disease.
SummaryA thorough understanding of the biology of the dentine–pulp complex is essential to underp... more SummaryA thorough understanding of the biology of the dentine–pulp complex is essential to underpin new treatment approaches and maximize clinical impact for regenerative endodontics and minimally invasive vital pulp treatment (VPT) strategies. Following traumatic and carious injury to dentine–pulp, a complex interplay between infection, inflammation and the host defence responses will occur, which is critical to tissue outcomes. Diagnostic procedures aim to inform treatment planning; however, these remain clinically subjective and have considerable limitations. As a consequence, significant effort has focussed on identification of diagnostic biomarkers, although these are also problematic due to difficulties in identifying appropriate diagnostic fluid sources and selecting reproducible biomarkers. This is further compounded by the link between inflammation and repair as many of the molecules involved exhibit significant multifunctionality. The tertiary dentine formed in response to...
AimTo establish whether irrigant activation techniques, namely manual dynamic activation (MDA), p... more AimTo establish whether irrigant activation techniques, namely manual dynamic activation (MDA), passive ultrasonic irrigation (PUI) and sonic irrigation (SI), improve the tubular penetration of sodium hypochlorite (NaOCl) into root dentine when compared with conventional needle irrigation (CNI). Secondly, investigate if increasing NaOCl concentration and/or contact time improves the performance of these techniques.MethodologyA total of 83 extracted human maxillary permanent canines were decoronated to 15 mm, and root canals prepared to a size 40, .10 taper. Root dentine was stained with crystal violet for 72 h and embedded in silicone. Eighty specimens were randomly distributed into 16 groups (n = 5) according to the irrigant activation technique, NaOCl concentration (2%; 5.25%) and irrigant contact time (10 min; 20 min). All activation techniques were used for 60 s in the last minute of irrigation. Additionally, three teeth were not exposed to NaOCl to confirm adequate dentine stai...
The DNA demethylating agent 5-aza-2’-deoxycytidine (DAC) has anti-cancer therapeutic potential, b... more The DNA demethylating agent 5-aza-2’-deoxycytidine (DAC) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how common analgesic paracetamol can augment the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC treatment specifically upregulates cyclooxygenase-2-prostaglandin E2 pathway, inadvertently providing cancer cells with survival potential, while the addition of paracetamol offsets this effect. Secondly, in the presence of paracetamol, DAC leads to glutathione depletion and ROS accumulation. Finally, this oxidative stress is further enhanced by DAC suppressing anti-oxidant and thioredoxin responses. Analyses of TCGA datasets show that the DAC/paracetamol combination targets pathways of clinical importance in many cancers. The benefits of combined treatment are demonstrated here in head and neck squamous c...
Dentin consists of inorganic hard tissue and organic dentin matrix components (DMCs). Various kin... more Dentin consists of inorganic hard tissue and organic dentin matrix components (DMCs). Various kinds of bioactive molecules are included in DMCs and some of them can be released after digestion by endogenous matrix metalloproteinases (MMPs) in the caries region. Digested DMCs induced by MMP20 have been reported to promote pulpal wound healing processes, but the released critical molecules responsible for this phenomenon are unclear. Here, we identified protein S100-A7 as a critical molecule for pulpal healing in digested DMCs by comprehensive proteomic approaches and following pulp capping experiments in rat molars. In addition, immunohistochemical results indicated the specific distribution of S100-A7 and receptor for advanced glycation end-products (RAGE) as receptor for S100-A7 in the early stage of the pulpal healing process, and following accumulation of CD146-positive stem cells in wounded pulp. Our findings indicate that protein S100-A7 released from dentin by MMP20 might play...
was reduced to 93.97% clinical and 88.39% radiographic success at 36 months follow-up. Results fr... more was reduced to 93.97% clinical and 88.39% radiographic success at 36 months follow-up. Results from the only comparative clinical trial showed pulpotomy to have comparable success to root canal treatment at 12, 24 and 60 month follow-up. Conclusions The evidence suggests high success for pulpotomy for teeth with signs and symptoms of irreversible pulpitis, however, results are based on heterogeneous studies with high risk of bias. Well-designed, adequately powered randomised controlled trials are required for evidence to change clinical practice. Clinical significance: Management of carious teeth with irreversible pulpitis is traditionally invasive, but emerging evidence suggests potentially successful treatment outcomes with less invasive therapies such as coronal pulpotomy
Photochemical & Photobiological Sciences, 2019
Photobiomodulation (PBM) describes the application of light at wavelengths ranging from 400–1100 ... more Photobiomodulation (PBM) describes the application of light at wavelengths ranging from 400–1100 nm to promote tissue healing, reduce inflammation and promote analgesia.
Objectives. The use of rheological properties to determine the optimal water: powder ratio of tri... more Objectives. The use of rheological properties to determine the optimal water: powder ratio of tricalcium silicate-based prototype materials incorporating alternative radiopacifiers and fillers. Determination of how the proportion of water incorporated affected the physicochemical behaviour of the materials. Methods. Endodontic cements replaced with 30% radio-opacifier, and additions of calcium phosphate and micro-silica were tested. The unmodified cements were mixed with a 0.35 water: powder ratio which served as control. At this water: powder ratio, the paste had an adequate clinical consistency and furthermore these pastes have been well characterized. Assessment of material rheological properties enabled adjustment of the water: powder ratio in each material to provide comparable viscosity values to those of the controls. The flowability, phase analysis and calcium release were measured for both viscosity-matched and the standard 0.35 water: powder ratio blends. The prototype materials with the adjusted water ratio were also characterized by scanning electron microscopy, energydispersive spectroscopy and evaluated for radio-opacity. Results. The use of the 0.35 water: powder ratio is not appropriate when changing the radiopacifier and incorporating additives. Zirconium oxide did not vary the water: powder ratio but tantalum oxide and calcium tungstate resulted in an increase and decrease in water demand respectively. Using the standard 0.35 ratio when the mixture had a low water demand resulted in higher flowability values and calcium release in solution. Micro-silica and calcium phosphate altered the hydration of the materials. All materials were adequately radiopaque.
AimThe primary aim was to identify techniques used to sample and analyse periradicular tissue flu... more AimThe primary aim was to identify techniques used to sample and analyse periradicular tissue fluid (PTF) in permanent teeth diagnosed with apical disease during root canal treatment. Secondly, to identify the types of inflammatory mediators studied using this approach.MethodologyData Sources: PubMed, EMBASE, Cochrane Library, Science Direct, Web of Science and OpenGrey. Eligibility Criteria: Clinical studies published until 1 June 2018 which utilized orthograde techniques to sample and analyse PTF were included. Cell culture, laboratory or animal studies and those concerned with investigating inflammatory mediator activity from within healthy or diseased pulp tissue, and not periradicular tissues, were excluded. Study appraisal and methods: In accordance with PRISMA guidelines, data were extracted on study characteristics, target mediators, sampling and assay techniques and the parameters associated with the PTF sampling and eluting protocol. A qualitative synthesis was conducted, ...
Dental pulp is known to be an accessible and important source of multipotent mesenchymal progenit... more Dental pulp is known to be an accessible and important source of multipotent mesenchymal progenitor cells termed dental pulp stem cells (DPSCs). DPSCs can differentiate into odontoblast-like cells and maintain pulp homeostasis by the formation of new dentin which protects the underlying pulp. DPSCs similar to other mesenchymal stem cells (MSCs) reside in a niche, a complex microenvironment consisting of an extracellular matrix, other local cell types and biochemical stimuli that influence the decision between stem cell (SC) self-renewal and differentiation. In addition to biochemical factors, mechanical factors are increasingly recognized as key regulators in DPSC behavior and function. Thus, microenvironments can significantly influence the role and differentiation of DPSCs through a combination of factors which are biochemical, biomechanical and biophysical in nature. Under in vitro conditions, it has been shown that DPSCs are sensitive to different types of force, such as uniaxial mechanical stretch, cyclic tensile strain, pulsating fluid flow, low-intensity pulsed ultrasound as well as being responsive to biomechanical cues presented in the form of micro-and nano-scale surface topographies. To understand how DPSCs sense and respond to the mechanics of their microenvironments, it is essential to determine how these cells convert mechanical and physical stimuli into function, including lineage specification. This review therefore covers some aspects of DPSC mechanoresponsivity with an emphasis on the factors that influence their behavior. An in-depth understanding of the physical environment that influence DPSC fate is necessary to improve the outcome of their therapeutic application for tissue regeneration.
Clinical Approaches in Endodontic Regeneration, 2018
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrat... more the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
Photochemical & Photobiological Sciences, 2021
Mesenchymal stem cells (MSCs) and photobiomodulation (PBM) both offer significant therapeutic pot... more Mesenchymal stem cells (MSCs) and photobiomodulation (PBM) both offer significant therapeutic potential in regenerative medicine. MSCs have the ability to self-renew and differentiate; giving rise to multiple cellular and tissue lineages that are utilised in repair and regeneration of damaged tissues. PBM utilises light energy delivered at a range of wavelengths to promote wound healing. The positive effects of light on MSC proliferation are well documented; and recently, several studies have determined the outcomes of PBM on mineralised tissue differentiation in MSC populations. As PBM effects are biphasic, it is important to understand the underlying cellular regulatory mechanisms, as well as, provide accurate details of the irradiation conditions, to optimise and standardise outcomes. This review article focuses on the use of red, near-infra-red (R/NIR) and blue wavelengths to promote the mineralisation potential of MSCs; and also reports on the possible molecular mechanisms whic...
Where a licence is displayed above, please note the terms and conditions of the licence govern yo... more Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Air-liquid interface (ALI) cultures are used to produce stratified epithelial tissues in vitro, n... more Air-liquid interface (ALI) cultures are used to produce stratified epithelial tissues in vitro, notably for the production of oral mucosal equivalents. Currently, there are few purpose-built devices, which aim to enhance the ease and reproducibility of generating such tissue. Most ALI cultures utilize stainless steel grids or cell culture inserts to elevate the matrix or scaffold to the surface of the culture media. In this study, a novel buoyant epithelial culture device (BECD) was designed to both contain a fibroblast-seeded collagen hydrogel and float in culture media, thereby automatically maintaining the ALI without further user intervention. BECDs aim to mitigate several issues associated with ALI culture; reducing the chance of media flooding the epithelial layer from physical disturbance, reducing technique sensitivity for less-experienced users, and improving the reproducibility of the epithelia generated. H400 oral squamous cell carcinoma cells cultured in BECDs for 7, 14, and 21 days showed continuous increase in epithelial tissue thickness with expected localization of epithelial differentiation markers: cytokeratin 5, involucrin, and E-cadherin. Fused filament fabrication three-dimensional printing with polypropylene used in BECD production allows for rapid turnover and design iteration, presenting a versatile, adaptable, and useful tool for application in in vitro cell culture.
Background Human dental pulp stem cells (hDPSCs) have received widespread attention in the fields... more Background Human dental pulp stem cells (hDPSCs) have received widespread attention in the fields of tissue engineering and regenerative medicine. Although amphiregulin (AREG) has been shown to play a vital function in the biological processes of various cell types, its effects on DPSCs remain largely unknown. The aim of this study was to explore the specific role of AREG as a biologically active factor in the regeneration of dental pulp tissue. Methods The growth of hDPSCs, together with their proliferation and apoptosis, in response to AREG was examined by CCK-8 assay and flow cytometry. We explored the effects of AREG on osteo/odontogenic differentiation in vitro and investigated the regeneration and mineralization of hDPSCs in response to AREG in vivo. The effects of AREG gain- and loss-of-function on DPSC differentiation were investigated following transfection using overexpression plasmids and shRNA, respectively. The involvement of the mitogen-activated protein kinase (MAPK) ...
Dental stem cells (DSCs) holds the ability to differentiate into numerous cell types. This proper... more Dental stem cells (DSCs) holds the ability to differentiate into numerous cell types. This property makes these cells particularly appropriate for therapeutic use in regenerative medicine. We report evidence that when DSCs undergo osteogenic differentiation, the osteoblast-like cells can be reverted back to a stem-like state and then further differentiated toward the osteogenic phenotype again, without gene manipulation. We have investigated two different MSCs types, both from dental tissues: dental follicle progenitor stem cells (DFPCs) and dental pulp stem cells (DPSCs). After osteogenic differentiation, both DFPCs and DPSCs can be reverted to a naïve stem cell-like status; importantly, dedifferentiated DSCs showed a greater potential to further differentiate toward the osteogenic phenotype. Our report aims to demonstrate for the first time that it is possible, under physiological conditions, to control the dedifferentiation of DSCs and that the rerouting of cell fate could potent...
The recent discovery of mesenchymal stem cells within periapical lesions (PL-MSC) has presented n... more The recent discovery of mesenchymal stem cells within periapical lesions (PL-MSC) has presented novel opportunities for managing periradicular diseases in adult teeth by way of enhancing tissue regeneration. This discovery coincides with the current paradigm shift toward biologically driven treatment strategies in endodontics, which have typically been reserved for non-vital immature permanent teeth. One such approach that shows promise is utilizing local endogenous non-collagenous dentine extracellular matrix components (dECM) to recruit and upregulate the intrinsic regenerative capacity of PL-MSCs in situ. At picogram levels, these morphogens have demonstrated tremendous ability to enhance the cellular activities in in vitro and in vivo animal studies that would otherwise be necessary for periradicular regeneration. Briefly, these include proliferation, viability, migration, differentiation, and mineralization. Therefore, topical application of dECMs during ortho-or retrograde root canal treatment could potentially enhance and sustain the regenerative mechanisms within diseased periapical tissues that are responsible for attaining favorable clinical and radiographic outcomes. This would provide many advantages when compared with conventional antimicrobial-only therapies for apical periodontitis (AP), which do not directly stimulate healing and have had stagnant success rates over the past five decades despite significant advances in operative techniques. The aim of this narrative review was to present the novel concept of exploiting endogenous dECMs as clinical tools for treating AP in mature permanent teeth. A large scope of literature was summarized to discuss the issues associated with conventional treatment modalities; current knowledge surrounding PL-MSCs; composition of the dECM; inductive potentials of dECM morphogens in other odontogenic stem cell niches; how treatment protocols can be adapted to take advantage of dECMs and PL-MSCs; and finally, the challenges currently impeding successful clinical translation alongside directions for future research.
Caries results in the demineralization and destruction of enamel and dentine, and as the disease ... more Caries results in the demineralization and destruction of enamel and dentine, and as the disease progresses, irreversible pulpitis can occur. Vital pulp therapy (VPT) is directed towards pulp preservation and the prevention of the progression of inflammation. The outcomes of VPT are not always predictable, and there is often a poor correlation between clinical signs and symptoms, and the events occurring at a molecular level. The inflamed pulp expresses increased levels of cytokines, including tumour necrosis factor (TNF)a, interleukin (IL)-1a, IL-1b, IL-4, IL-6, IL-8, IL-17 and IL-23, which recruit and drive a complex cellular immune response. Chronic inflammation and sustained cytokine release can result in irreversible pulp damage and a decreased capacity for tissue healing. Other chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases and rheumatoid arthritis, are also characterized by an dysregulated immune response composed of relatively high cytokine levels and increased numbers of immune cells along with microbial and hard-soft tissue destructive pathologies. Whilst anti-cytokine therapies have been successfully applied in the treatment of these diseases, this approach is yet to be attempted in cases of pulp inflammation. This review therefore focuses on the similarities in the aetiology between chronic inflammatory diseases and pulpitis, and explores how anticytokine therapies could be applied to manage an inflamed pulp and facilitate healing. Further proof-ofconcept studies and clinical trials are justified to determine the effectiveness of these treatments to enable more predictable outcomes in VPT.
Research over several decades has increased our understanding of the nature of reparative and reg... more Research over several decades has increased our understanding of the nature of reparative and regenerative processes in the dental pulp, at both the cellular and molecular level. However, advances in scientific knowledge have not translated into novel clinical treatment strategies for caries-induced pulpitis. This narrative review explores the evidence regarding the ability of inflamed pulp tissue to heal and how this knowledge may be used therapeutically. A literature search and evidence analysis covering basic, translational and clinical pulp biology research was performed. The review focuses on (1) the regenerative and defense capabilities of the pulp during caries-induced inflammation; (2) the potential of novel biomaterials to harness the reparative and regenerative functions of the inflamed pulp; and (3) future perspectives and opportunities for conservative management of the inflamed pulp. Current conservative management strategies for pulpitis are limited by a combination of...
Where a licence is displayed above, please note the terms and conditions of the licence govern yo... more Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Journal of Ege University School of Dentistry, 2020
Boron is a bioactive trace element found in humans and essential for the growth and maintenance o... more Boron is a bioactive trace element found in humans and essential for the growth and maintenance of bone and also has reported anti-inflammatory and antimicrobial activity. Boric acid is a well-characterised boron-containing compound which reportedly can reduce periodontal inflammation. Thus, the aim of the current study was to evaluate the possible bactericidal and/or bacteriostatic effects of boric acid on the periodontal pathogens: Fusobacterium nucleatum and Porphyromonas gingivalis. Materials and Methods: Minimum inhibitory concentration (MIC) of boric acid on F. nucleatum (ATCC 10953) and P. gingivalis (ATCC 33277) were determined by the broth microdilution method. Overnight cultures were diluted to the following starting concentrations: 5x10 5 cfu/ml for F. nucleatum and 5x10 6 cfu/ml for P. gingivalis. After incubation for 48h at 37°C in an anaerobic cabinet the absorbance of the cultures was measured. The minimum bactericidal concentration (MBC) was determined by plating an aliquot of the cell suspensions on agar plates, and bacteria were counted after incubation at 37°C for 48 h under anaerobic conditions. Results: Boric acid was able to inhibit the growth of F. nucleatum at a concentration of 780 nM and P. gingivalis at a concentration of 1.56 µM. The MBC of boric acid was 19 mM for F. nucleatum however using tested concentrations (75 mM-1nm) were insufficient to provide an MBC for P. gingivalis. Conclusion: Boric acid may be a possible candidate for providing local antimicrobial actions on periodontal pathogens and therefore may have potential as a therapeutic intervention in the management of periodontal disease.
SummaryA thorough understanding of the biology of the dentine–pulp complex is essential to underp... more SummaryA thorough understanding of the biology of the dentine–pulp complex is essential to underpin new treatment approaches and maximize clinical impact for regenerative endodontics and minimally invasive vital pulp treatment (VPT) strategies. Following traumatic and carious injury to dentine–pulp, a complex interplay between infection, inflammation and the host defence responses will occur, which is critical to tissue outcomes. Diagnostic procedures aim to inform treatment planning; however, these remain clinically subjective and have considerable limitations. As a consequence, significant effort has focussed on identification of diagnostic biomarkers, although these are also problematic due to difficulties in identifying appropriate diagnostic fluid sources and selecting reproducible biomarkers. This is further compounded by the link between inflammation and repair as many of the molecules involved exhibit significant multifunctionality. The tertiary dentine formed in response to...
AimTo establish whether irrigant activation techniques, namely manual dynamic activation (MDA), p... more AimTo establish whether irrigant activation techniques, namely manual dynamic activation (MDA), passive ultrasonic irrigation (PUI) and sonic irrigation (SI), improve the tubular penetration of sodium hypochlorite (NaOCl) into root dentine when compared with conventional needle irrigation (CNI). Secondly, investigate if increasing NaOCl concentration and/or contact time improves the performance of these techniques.MethodologyA total of 83 extracted human maxillary permanent canines were decoronated to 15 mm, and root canals prepared to a size 40, .10 taper. Root dentine was stained with crystal violet for 72 h and embedded in silicone. Eighty specimens were randomly distributed into 16 groups (n = 5) according to the irrigant activation technique, NaOCl concentration (2%; 5.25%) and irrigant contact time (10 min; 20 min). All activation techniques were used for 60 s in the last minute of irrigation. Additionally, three teeth were not exposed to NaOCl to confirm adequate dentine stai...
The DNA demethylating agent 5-aza-2’-deoxycytidine (DAC) has anti-cancer therapeutic potential, b... more The DNA demethylating agent 5-aza-2’-deoxycytidine (DAC) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how common analgesic paracetamol can augment the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC treatment specifically upregulates cyclooxygenase-2-prostaglandin E2 pathway, inadvertently providing cancer cells with survival potential, while the addition of paracetamol offsets this effect. Secondly, in the presence of paracetamol, DAC leads to glutathione depletion and ROS accumulation. Finally, this oxidative stress is further enhanced by DAC suppressing anti-oxidant and thioredoxin responses. Analyses of TCGA datasets show that the DAC/paracetamol combination targets pathways of clinical importance in many cancers. The benefits of combined treatment are demonstrated here in head and neck squamous c...
Dentin consists of inorganic hard tissue and organic dentin matrix components (DMCs). Various kin... more Dentin consists of inorganic hard tissue and organic dentin matrix components (DMCs). Various kinds of bioactive molecules are included in DMCs and some of them can be released after digestion by endogenous matrix metalloproteinases (MMPs) in the caries region. Digested DMCs induced by MMP20 have been reported to promote pulpal wound healing processes, but the released critical molecules responsible for this phenomenon are unclear. Here, we identified protein S100-A7 as a critical molecule for pulpal healing in digested DMCs by comprehensive proteomic approaches and following pulp capping experiments in rat molars. In addition, immunohistochemical results indicated the specific distribution of S100-A7 and receptor for advanced glycation end-products (RAGE) as receptor for S100-A7 in the early stage of the pulpal healing process, and following accumulation of CD146-positive stem cells in wounded pulp. Our findings indicate that protein S100-A7 released from dentin by MMP20 might play...
was reduced to 93.97% clinical and 88.39% radiographic success at 36 months follow-up. Results fr... more was reduced to 93.97% clinical and 88.39% radiographic success at 36 months follow-up. Results from the only comparative clinical trial showed pulpotomy to have comparable success to root canal treatment at 12, 24 and 60 month follow-up. Conclusions The evidence suggests high success for pulpotomy for teeth with signs and symptoms of irreversible pulpitis, however, results are based on heterogeneous studies with high risk of bias. Well-designed, adequately powered randomised controlled trials are required for evidence to change clinical practice. Clinical significance: Management of carious teeth with irreversible pulpitis is traditionally invasive, but emerging evidence suggests potentially successful treatment outcomes with less invasive therapies such as coronal pulpotomy
Photochemical & Photobiological Sciences, 2019
Photobiomodulation (PBM) describes the application of light at wavelengths ranging from 400–1100 ... more Photobiomodulation (PBM) describes the application of light at wavelengths ranging from 400–1100 nm to promote tissue healing, reduce inflammation and promote analgesia.
Objectives. The use of rheological properties to determine the optimal water: powder ratio of tri... more Objectives. The use of rheological properties to determine the optimal water: powder ratio of tricalcium silicate-based prototype materials incorporating alternative radiopacifiers and fillers. Determination of how the proportion of water incorporated affected the physicochemical behaviour of the materials. Methods. Endodontic cements replaced with 30% radio-opacifier, and additions of calcium phosphate and micro-silica were tested. The unmodified cements were mixed with a 0.35 water: powder ratio which served as control. At this water: powder ratio, the paste had an adequate clinical consistency and furthermore these pastes have been well characterized. Assessment of material rheological properties enabled adjustment of the water: powder ratio in each material to provide comparable viscosity values to those of the controls. The flowability, phase analysis and calcium release were measured for both viscosity-matched and the standard 0.35 water: powder ratio blends. The prototype materials with the adjusted water ratio were also characterized by scanning electron microscopy, energydispersive spectroscopy and evaluated for radio-opacity. Results. The use of the 0.35 water: powder ratio is not appropriate when changing the radiopacifier and incorporating additives. Zirconium oxide did not vary the water: powder ratio but tantalum oxide and calcium tungstate resulted in an increase and decrease in water demand respectively. Using the standard 0.35 ratio when the mixture had a low water demand resulted in higher flowability values and calcium release in solution. Micro-silica and calcium phosphate altered the hydration of the materials. All materials were adequately radiopaque.
AimThe primary aim was to identify techniques used to sample and analyse periradicular tissue flu... more AimThe primary aim was to identify techniques used to sample and analyse periradicular tissue fluid (PTF) in permanent teeth diagnosed with apical disease during root canal treatment. Secondly, to identify the types of inflammatory mediators studied using this approach.MethodologyData Sources: PubMed, EMBASE, Cochrane Library, Science Direct, Web of Science and OpenGrey. Eligibility Criteria: Clinical studies published until 1 June 2018 which utilized orthograde techniques to sample and analyse PTF were included. Cell culture, laboratory or animal studies and those concerned with investigating inflammatory mediator activity from within healthy or diseased pulp tissue, and not periradicular tissues, were excluded. Study appraisal and methods: In accordance with PRISMA guidelines, data were extracted on study characteristics, target mediators, sampling and assay techniques and the parameters associated with the PTF sampling and eluting protocol. A qualitative synthesis was conducted, ...
Dental pulp is known to be an accessible and important source of multipotent mesenchymal progenit... more Dental pulp is known to be an accessible and important source of multipotent mesenchymal progenitor cells termed dental pulp stem cells (DPSCs). DPSCs can differentiate into odontoblast-like cells and maintain pulp homeostasis by the formation of new dentin which protects the underlying pulp. DPSCs similar to other mesenchymal stem cells (MSCs) reside in a niche, a complex microenvironment consisting of an extracellular matrix, other local cell types and biochemical stimuli that influence the decision between stem cell (SC) self-renewal and differentiation. In addition to biochemical factors, mechanical factors are increasingly recognized as key regulators in DPSC behavior and function. Thus, microenvironments can significantly influence the role and differentiation of DPSCs through a combination of factors which are biochemical, biomechanical and biophysical in nature. Under in vitro conditions, it has been shown that DPSCs are sensitive to different types of force, such as uniaxial mechanical stretch, cyclic tensile strain, pulsating fluid flow, low-intensity pulsed ultrasound as well as being responsive to biomechanical cues presented in the form of micro-and nano-scale surface topographies. To understand how DPSCs sense and respond to the mechanics of their microenvironments, it is essential to determine how these cells convert mechanical and physical stimuli into function, including lineage specification. This review therefore covers some aspects of DPSC mechanoresponsivity with an emphasis on the factors that influence their behavior. An in-depth understanding of the physical environment that influence DPSC fate is necessary to improve the outcome of their therapeutic application for tissue regeneration.
Clinical Approaches in Endodontic Regeneration, 2018
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrat... more the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
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