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Molecular Advances in Dental Pulp Tissue Engineering

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 27099

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Prof. Dr. Matthias Widbiller

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Guest Editor

Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, D-93093 Regensburg, Germany
Interests: pulp biology; tissue engineering; dentin matrix proteins; dental pulp stem cells
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Kerstin M. Galler

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Guest Editor

Department of Operative Dentistry and Periodontology, Friedrich-Alexander-University Erlangen-Nuernberg, D-91054 Erlangen, Germany
Interests: pulp biology; tissue engineering; scaffold materials; dental pulp stem cells

Special Issue Information

Dear Colleagues,

Protected by the surrounding mineralized barriers, such as enamel, dentin and cementum, dental pulp is a functionally versatile tissue that fulfils various tasks. Besides the perception of thermal and mechanical stimuli as a warning system as well as the deposition of dentin, the pulp exerts a variety of immunological functions, in terms of both recognition and of defense. In young patients, a sound and functional dental pulp is indispensable for the completion of root development, and early pulp necrosis results in fracture-prone teeth with fragile root walls. Whether in young or adult patients, the loss of pulp tissue after caries or trauma requires therapeutic intervention by root canal treatment and filling with a synthetic material, which results in the loss of all its physiological functions.

In recent years, creative and multi-faceted attempts have been made to regenerate this valuable tissue using advanced molecular biology methods. Promising approaches based on tissue engineering and regenerative medicine (TERM) have been developed for this purpose. These stem-cell-based or primarily cell-free procedures use specifically customized scaffold materials and biologically active molecules to achieve true regeneration of the dental pulp in terms of both its architecture and function. Several of these approaches are already taking requirements for clinical application into consideration.

This Special Issue aims to present the scientific progress in this field of research. The goal is to collect innovative studies in the field of stem cell biology, scaffold material development or molecular signaling that contribute to the transfer of this knowledge from the bench to the dental clinic.

Prof. Dr. Matthias Widbiller
Prof. Dr. Kerstin M. Galler
Guest Editors

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Keywords

tissue engineering and regenerative medicine (TERM)
pulp regeneration
scaffold materials
stem cells
bioactive molecules
dentin matrix proteins

Published Papers (11 papers)

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Editorial

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7 pages, 3528 KiB

Open AccessEditorial

Engineering the Future of Dental Health: Exploring Molecular Advancements in Dental Pulp Regeneration

by Matthias Widbiller and Kerstin M. Galler

Int. J. Mol. Sci. 2023, 24(14), 11453; https://doi.org/10.3390/ijms241411453 - 14 Jul 2023

Cited by 1 | Viewed by 1200

Abstract

Protected by the surrounding mineralized barriers of enamel, dentin, and cementum, dental pulp is a functionally versatile tissue that fulfills multiple roles [...] Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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Research

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17 pages, 4326 KiB

Open AccessArticle

Kappa-Carrageenan/Chitosan/Gelatin Scaffolds Provide a Biomimetic Microenvironment for Dentin-Pulp Regeneration

by Konstantinos Loukelis, Foteini Machla, Athina Bakopoulou and Maria Chatzinikolaidou

Int. J. Mol. Sci. 2023, 24(7), 6465; https://doi.org/10.3390/ijms24076465 - 30 Mar 2023

Cited by 4 | Viewed by 2774

Abstract

This study aims to investigate the impact of kappa-carrageenan on dental pulp stem cells (DPSCs) behavior in terms of biocompatibility and odontogenic differentiation potential when it is utilized as a component for the production of 3D sponge-like scaffolds. For this purpose, we prepared three types of scaffolds by freeze-drying (i) kappa-carrageenan/chitosan/gelatin enriched with KCl (KCG-KCl) as a physical crosslinker for the sulfate groups of kappa-carrageenan, (ii) kappa-carrageenan/chitosan/gelatin (KCG) and (iii) chitosan/gelatin (CG) scaffolds as a control. The mechanical analysis illustrated a significantly higher elastic modulus of the cell-laden scaffolds compared to the cell-free ones after 14 and 28 days with values ranging from 25 to 40 kPa, showing an increase of 27–36%, with the KCG-KCl scaffolds indicating the highest and CG the lowest values. Cell viability data showed a significant increase from days 3 to 7 and up to day 14 for all scaffold compositions. Significantly increasing alkaline phosphatase (ALP) activity has been observed over time in all three scaffold compositions, while the KCG-KCl scaffolds indicated significantly higher calcium production after 21 and 28 days compared to the CG control. The gene expression analysis of the odontogenic markers DSPP, ALP and RunX2 revealed a two-fold higher upregulation of DSPP in KCG-KCl scaffolds at day 14 compared to the other two compositions. A significant increase of the RunX2 expression between days 7 and 14 was observed for all scaffolds, with a significantly higher increase of at least twelve-fold for the kappa-carrageenan containing scaffolds, which exhibited an earlier ALP gene expression compared to the CG. Our results demonstrate that the integration of kappa-carrageenan in scaffolds significantly enhanced the odontogenic potential of DPSCs and supports dentin-pulp regeneration. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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14 pages, 2082 KiB

Open AccessArticle

Bone Differentiation Ability of CD146-Positive Stem Cells from Human Exfoliated Deciduous Teeth

by Ryo Kunimatsu, Kodai Rikitake, Yuki Yoshimi, Nurul Aisyah Rizky Putranti, Yoko Hayashi and Kotaro Tanimoto

Int. J. Mol. Sci. 2023, 24(4), 4048; https://doi.org/10.3390/ijms24044048 - 17 Feb 2023

Cited by 5 | Viewed by 1726

Abstract

Regenerative therapy for tissues by mesenchymal stem cell (MSCs) transplantation has received much attention. The cluster of differentiation (CD)146 marker, a surface-antigen of stem cells, is crucial for angiogenic and osseous differentiation abilities. Bone regeneration is accelerated by the transplantation of CD146-positive deciduous dental pulp-derived mesenchymal stem cells contained in stem cells from human exfoliated deciduous teeth (SHED) into a living donor. However, the role of CD146 in SHED remains unclear. This study aimed to compare the effects of CD146 on cell proliferative and substrate metabolic abilities in a population of SHED. SHED was isolated from deciduous teeth, and flow cytometry was used to analyze the expression of MSCs markers. Cell sorting was performed to recover the CD146-positive cell population (CD146+) and CD146-negative cell population (CD146-). CD146 + SHED without cell sorting and CD146-SHED were examined and compared among three groups. To investigate the effect of CD146 on cell proliferation ability, an analysis of cell proliferation ability was performed using BrdU assay and MTS assay. The bone differentiation ability was evaluated using an alkaline phosphatase (ALP) stain after inducing bone differentiation, and the quality of ALP protein expressed was examined. We also performed Alizarin red staining and evaluated the calcified deposits. The gene expression of ALP, bone morphogenetic protein-2 (BMP-2), and osteocalcin (OCN) was analyzed using a real-time polymerase chain reaction. There was no significant difference in cell proliferation among the three groups. The expression of ALP stain, Alizarin red stain, ALP, BMP-2, and OCN was the highest in the CD146+ group. CD146 + SHED had higher osteogenic differentiation potential compared with SHED and CD146-SHED. CD146 contained in SHED may be a valuable population of cells for bone regeneration therapy. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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20 pages, 2390 KiB

Open AccessArticle

Transcriptome Analysis Reveals Modulation of Human Stem Cells from the Apical Papilla by Species Associated with Dental Root Canal Infection

by Yelyzaveta Razghonova, Valeriia Zymovets, Philip Wadelius, Olena Rakhimova, Lokeshwaran Manoharan, Malin Brundin, Peyman Kelk and Nelly Romani Vestman

Int. J. Mol. Sci. 2022, 23(22), 14420; https://doi.org/10.3390/ijms232214420 - 20 Nov 2022

Cited by 5 | Viewed by 1915

Abstract

Interaction of oral bacteria with stem cells from the apical papilla (SCAP) can negatively affect the success of regenerative endodontic treatment (RET). Through RNA-seq transcriptomic analysis, we studied the effect of the oral bacteria Fusobacterium nucleatum and Enterococcus faecalis, as well as their supernatants enriched by bacterial metabolites, on the osteo- and dentinogenic potential of SCAPs in vitro. We performed bulk RNA-seq, on the basis of which differential expression analysis (DEG) and gene ontology enrichment analysis (GO) were performed. DEG analysis showed that E. faecalis supernatant had the greatest effect on SCAPs, whereas F. nucleatum supernatant had the least effect (Tanimoto coefficient = 0.05). GO term enrichment analysis indicated that F. nucleatum upregulates the immune and inflammatory response of SCAPs, and E. faecalis suppresses cell proliferation and cell division processes. SCAP transcriptome profiles showed that under the influence of E. faecalis the upregulation of VEGFA, Runx2, and TBX3 genes occurred, which may negatively affect the SCAP’s osteo- and odontogenic differentiation. F. nucleatum downregulates the expression of WDR5 and TBX2 and upregulates the expression of TBX3 and NFIL3 in SCAPs, the upregulation of which may be detrimental for SCAPs’ differentiation potential. In conclusion, the present study shows that in vitro, F. nucleatum, E. faecalis, and their metabolites are capable of up- or downregulating the expression of genes that are necessary for dentinogenic and osteogenic processes to varying degrees, which eventually may result in unsuccessful RET outcomes. Transposition to the clinical context merits some reservations, which should be approached with caution. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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15 pages, 2896 KiB

Open AccessArticle

Electrospun Azithromycin-Laden Gelatin Methacryloyl Fibers for Endodontic Infection Control

by Afzan A. Ayoub, Abdel H. Mahmoud, Juliana S. Ribeiro, Arwa Daghrery, Jinping Xu, J. Christopher Fenno, Anna Schwendeman, Hajime Sasaki, Renan Dal-Fabbro and Marco C. Bottino

Int. J. Mol. Sci. 2022, 23(22), 13761; https://doi.org/10.3390/ijms232213761 - 9 Nov 2022

Cited by 9 | Viewed by 2076

Abstract

This study was aimed at engineering photocrosslinkable azithromycin (AZ)-laden gelatin methacryloyl fibers via electrospinning to serve as a localized and biodegradable drug delivery system for endodontic infection control. AZ at three distinct amounts was mixed with solubilized gelatin methacryloyl and the photoinitiator to obtain the following fibers: GelMA+5%AZ, GelMA+10%AZ, and GelMA+15%AZ. Fiber morphology, diameter, AZ incorporation, mechanical properties, degradation profile, and antimicrobial action against Aggregatibacter actinomycetemcomitans and Actinomyces naeslundii were also studied. In vitro compatibility with human-derived dental pulp stem cells and inflammatory response in vivo using a subcutaneous rat model were also determined. A bead-free fibrous microstructure with interconnected pores was observed for all groups. GelMA and GelMA+10%AZ had the highest fiber diameter means. The tensile strength of the GelMA-based fibers was reduced upon AZ addition. A similar pattern was observed for the degradation profile in vitro. GelMA+15%AZ fibers led to the highest bacterial inhibition. The presence of AZ, regardless of the concentration, did not pose significant toxicity. In vivo findings indicated higher blood vessel formation, mild inflammation, and mature and thick well-oriented collagen fibers interweaving with the engineered fibers. Altogether, AZ-laden photocrosslinkable GelMA fibers had adequate mechanical and degradation properties, with 15%AZ displaying significant antimicrobial activity without compromising biocompatibility. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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14 pages, 3812 KiB

Open AccessArticle

Human Amnion Epithelial Cells: A Potential Cell Source for Pulp Regeneration?

by Cristina Bucchi, Ella Ohlsson, Josep Maria de Anta, Melanie Woelflick, Kerstin Galler, María Cristina Manzanares-Cespedes and Matthias Widbiller

Int. J. Mol. Sci. 2022, 23(5), 2830; https://doi.org/10.3390/ijms23052830 - 4 Mar 2022

Cited by 3 | Viewed by 1960

Abstract

The aim of this study was to analyze the suitability of pluripotent stem cells derived from the amnion (hAECs) as a potential cell source for revitalization in vitro. hAECs were isolated from human placentas, and dental pulp stem cells (hDPSCs) and dentin matrix proteins (eDMPs) were obtained from human teeth. Both hAECs and hDPSCs were cultured with 10% FBS, eDMPs and an osteogenic differentiation medium (StemPro). Viability was assessed by MTT and cell adherence to dentin was evaluated by scanning electron microscopy. Furthermore, the expression of mineralization-, odontogenic differentiation- and epithelial–mesenchymal transition-associated genes was analyzed by quantitative real-time PCR, and mineralization was evaluated through Alizarin Red staining. The viability of hAECs was significantly lower compared with hDPSCs in all groups and at all time points. Both hAECs and hDPSCs adhered to dentin and were homogeneously distributed. The regulation of odontoblast differentiation- and mineralization-associated genes showed the lack of transition of hAECs into an odontoblastic phenotype; however, genes associated with epithelial–mesenchymal transition were significantly upregulated in hAECs. hAECs showed small amounts of calcium deposition after osteogenic differentiation with StemPro. Pluripotent hAECs adhere on dentin and possess the capacity to mineralize. However, they presented an unfavorable proliferation behavior and failed to undergo odontoblastic transition. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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18 pages, 2231 KiB

Open AccessArticle

Molecular Biological Comparison of Dental Pulp- and Apical Papilla-Derived Stem Cells

by Martyna Smeda, Kerstin M. Galler, Melanie Woelflick, Andreas Rosendahl, Christoph Moehle, Beate Lenhardt, Wolfgang Buchalla and Matthias Widbiller

Int. J. Mol. Sci. 2022, 23(5), 2615; https://doi.org/10.3390/ijms23052615 - 27 Feb 2022

Cited by 12 | Viewed by 2453

Abstract

Both the dental pulp and the apical papilla represent a promising source of mesenchymal stem cells for regenerative endodontic protocols. The aim of this study was to outline molecular biological conformities and differences between dental pulp stem cells (DPSC) and stem cells from the apical papilla (SCAP). Thus, cells were isolated from the pulp and the apical papilla of an extracted molar and analyzed for mesenchymal stem cell markers as well as multi-lineage differentiation. During induced osteogenic differentiation, viability, proliferation, and wound healing assays were performed, and secreted signaling molecules were quantified by enzyme-linked immunosorbent assays (ELISA). Transcriptome-wide gene expression was profiled by microarrays and validated by quantitative reverse transcription PCR (qRT-PCR). Gene regulation was evaluated in the context of culture parameters and functionality. Both cell types expressed mesenchymal stem cell markers and were able to enter various lineages. DPSC and SCAP showed no significant differences in cell viability, proliferation, or migration; however, variations were observed in the profile of secreted molecules. Transcriptome analysis revealed the most significant gene regulation during the differentiation period, and 13 biomarkers were identified whose regulation was essential for both cell types. DPSC and SCAP share many features and their differentiation follows similar patterns. From a molecular biological perspective, both seem to be equally suitable for dental pulp tissue engineering. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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15 pages, 2228 KiB

Open AccessArticle

Engineering of Injectable Antibiotic-laden Fibrous Microparticles Gelatin Methacryloyl Hydrogel for Endodontic Infection Ablation

by Juliana S. Ribeiro, Eliseu A. Münchow, Ester A. F. Bordini, Nathalie S. Rodrigues, Nileshkumar Dubey, Hajime Sasaki, John C. Fenno, Steven Schwendeman and Marco C. Bottino

Int. J. Mol. Sci. 2022, 23(2), 971; https://doi.org/10.3390/ijms23020971 - 16 Jan 2022

Cited by 20 | Viewed by 3167

Abstract

This study aimed at engineering cytocompatible and injectable antibiotic-laden fibrous microparticles gelatin methacryloyl (GelMA) hydrogels for endodontic infection ablation. Clindamycin (CLIN) or metronidazole (MET) was added to a polymer solution and electrospun into fibrous mats, which were processed via cryomilling to obtain CLIN- or MET-laden fibrous microparticles. Then, GelMA was modified with CLIN- or MET-laden microparticles or by using equal amounts of each set of fibrous microparticles. Morphological characterization of electrospun fibers and cryomilled particles was performed via scanning electron microscopy (SEM). The experimental hydrogels were further examined for swelling, degradation, and toxicity to dental stem cells, as well as antimicrobial action against endodontic pathogens (agar diffusion) and biofilm inhibition, evaluated both quantitatively (CFU/mL) and qualitatively via confocal laser scanning microscopy (CLSM) and SEM. Data were analyzed using ANOVA and Tukey’s test (α = 0.05). The modification of GelMA with antibiotic-laden fibrous microparticles increased the hydrogel swelling ratio and degradation rate. Cell viability was slightly reduced, although without any significant toxicity (cell viability > 50%). All hydrogels containing antibiotic-laden fibrous microparticles displayed antibiofilm effects, with the dentin substrate showing nearly complete elimination of viable bacteria. Altogether, our findings suggest that the engineered injectable antibiotic-laden fibrous microparticles hydrogels hold clinical prospects for endodontic infection ablation. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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Review

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19 pages, 2578 KiB

Open AccessReview

A Compilation of Study Models for Dental Pulp Regeneration

by Ella Ohlsson, Kerstin M. Galler and Matthias Widbiller

Int. J. Mol. Sci. 2022, 23(22), 14361; https://doi.org/10.3390/ijms232214361 - 18 Nov 2022

Cited by 4 | Viewed by 2602

Abstract

Efforts to heal damaged pulp tissue through tissue engineering have produced positive results in pilot trials. However, the differentiation between real regeneration and mere repair is not possible through clinical measures. Therefore, preclinical study models are still of great importance, both to gain insights into treatment outcomes on tissue and cell levels and to develop further concepts for dental pulp regeneration. This review aims at compiling information about different in vitro and in vivo ectopic, semiorthotopic, and orthotopic models. In this context, the differences between monolayer and three-dimensional cell cultures are discussed, a semiorthotopic transplantation model is introduced as an in vivo model for dental pulp regeneration, and finally, different animal models used for in vivo orthotopic investigations are presented. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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11 pages, 1055 KiB

Open AccessReview

Modulators of Wnt Signaling Pathway Implied in Dentin Pulp Complex Engineering: A Literature Review

by Marion Florimond, Sandra Minic, Paul Sharpe, Catherine Chaussain, Emmanuelle Renard and Tchilalo Boukpessi

Int. J. Mol. Sci. 2022, 23(18), 10582; https://doi.org/10.3390/ijms231810582 - 13 Sep 2022

Cited by 3 | Viewed by 2197

Abstract

The main goal of vital pulp therapy (VPT) is to preserve the vitality of the pulp tissue, even when it is exposed due to bacterial invasion, iatrogenic mechanical preparation, or trauma. The type of new dentin formed as a result of VPT can differ in its cellular origin, its microstructure, and its barrier function. It is generally agreed that the new dentin produced by odontoblasts (reactionary dentin) has a tubular structure, while the dentin produced by pulp cells (reparative dentin) does not or has less. Thus, even VPT aims to maintain the vitality of the pulp. It does not regenerate the dentin pulp complex integrity. Therefore, many studies have sought to identify new therapeutic strategies to successfully regenerate the dentin pulp complex. Among them is a Wnt protein-based strategy based on the fact that Wnt proteins seem to be powerful stem cell factors that allow control of the self-renewal and proliferation of multiple adult stem cell populations, suitable for homeostasis maintenance, tissue healing, and regeneration promotion. Thus, this review outlines the different agents targeting the Wnt signaling that could be applied in a tooth environment, and could be a potential therapy for dentin pulp complex and bone regeneration. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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28 pages, 3249 KiB

Open AccessReview

Tissue Characteristics in Endodontic Regeneration: A Systematic Review

by Sandra Minic, Sibylle Vital, Catherine Chaussain, Tchilalo Boukpessi and Francesca Mangione

Int. J. Mol. Sci. 2022, 23(18), 10534; https://doi.org/10.3390/ijms231810534 - 11 Sep 2022

Cited by 1 | Viewed by 3231

Abstract

The regenerative endodontic procedure (REP) represents a treatment option for immature necrotic teeth with a periapical lesion. Currently, this therapy has a wide field of pre-clinical and clinical applications, but no standardization exists regarding successful criteria. Thus, by analysis of animal and human studies, the aim of this systematic review was to highlight the main characteristics of the tissue generated by REP. A customized search of PubMed, EMBASE, Scopus, and Web of Science databases from January 2000 to January 2022 was conducted. Seventy-five human and forty-nine animal studies were selected. In humans, the evaluation criteria were clinical 2D and 3D radiographic examinations. Most of the studies identified a successful REP with an asymptomatic tooth, apical lesion healing, and increased root thickness and length. In animals, histological and radiological criteria were considered. Newly formed tissues in the canals were fibrous, cementum, or bone-like tissues along the dentine walls depending on the area of the root. REP assured tooth development and viability. However, further studies are needed to identify procedures to successfully reproduce the physiological structure and function of the dentin–pulp complex. Full article

(This article belongs to the Special Issue Molecular Advances in Dental Pulp Tissue Engineering)

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