INTRODUCTION:

Dental caries is the biggest dental problem in the world with an incidence of 95%.^1,2Caries is a disease with a multifactorial etiology including host, agent, substrate, time and environment factors. Agent factors include the cariogenic bacteria such as Scardovia wiggsiae, Streptococcus mutans, Streptococcus sanguinus, Actinomyces sp., and Lactobacillus sp. Microbial dysbiosis on the tooth surface and fermentation of carbohydrates to acid acts as substrate factors. The time factor affects the prolonged imbalance between demineralization and remineralization cycles of the tooth tissue. Environmental factors include the level of education regarding how to maintain oral health, socio-economics, and culture of a person or caregiver.^3-9 Caries lesions can occur on enamel, dentin, or both of them.¹⁰ Demineralization of the dentin near the pulp at a distance of 0.5 mm to 1 mm causes a chronic inflammatory reaction in the subodontoblastic area. Untreated caries can lead to complications in the form of tooth loss.^11-13

One of the innovative dentin remineralization agents from biomaterials is a combination of proanthocyanidin and polyamidoamine-calcium phosphate nanoparticles which is applied topically to pulp capping to induce dentinogenesis. Proanthocyanidin (PA) is the main bioactive compound from grape seeds as antibacterial, antioxidant, and anti-inflammatory.¹⁴ Polyamidoamine (PAMAM) is a dendrimer with high nucleation capability as a biomineralizer of dental tissue.¹⁵Calcium phosphate (CP) nanoparticles are drug carriers combined with PAMAM to increase the strength of dental tissue and inhibit the development of caries. The combination of PA and PAMAM-CP nanoparticles as dental pulp capping material has the potential to regenerate dentin tissue in dental caries. Furthermore, the aim of this narrative review is to describe the combination of PA and PAMAM-CP nanoparticles as pulp capping biomaterial for dentin regeneration in dental caries.

Histology of Caries Lesions:

Caries is a chronic demineralization of dental tissue due to the interaction between host, agents, environment, and time. Caries is the metabolic activity of the colonization of Streptococcus mutans bacteria on the tooth surface with a supportive and persistent environmental condition for a long time. In 1980, Takao Fusayama released his team's study on the analysis of caries lesions at Tokyo Medical and Dental University.

The researchers were able to differentiate two layers in a caries lesion that were quite distinct in origin using histologic, biochemical, biomechanical, microscopic, and microbiologic methods.¹⁶ Demineralized tooth lesions in the early stages can be stopped or is reversible. The low immunity of host and low salivary secretion also may increase the progression of dental caries.^17,18 Dental minerals consist of pure calcium phosphate-hydroxyapatite ions and can quickly dissolve when the pH level of the oral cavity decreases. The pH level of the oral cavity which is conditioned near to neutral contributes to the re-deposit of mineral ions in carious lesions, this activity is called remineralization.^19-21 One of the main remineralization agents is fluoride which is able to reduce the solubility of tooth minerals and increase the hydroxyapatite ion, thereby providing a strong caries prevention effect. The pH imbalance in the oral cavity that occurs continuously supports demineralization which results in the lesion developing and damaging the tooth structures including dentin, enamel, and perforation of the pulp chamber. At this stage, the caries lesion cannot be stopped or is irreversible. The treatment required are restoration, pulp capping, or tooth extraction based on case.^22,23

Pulp Capping:

The open cavity that reaches the pulp vital conditions needs to be treated by administering medicaments to the pulp, which is called pulp capping.^24-27 Deep cavity if not treated results in loss of tooth vitality and decreased caries defense mechanisms, susceptibility to fracture, discoloration and decreased ability of regenerative therapy for complex pulp-dentin. The goal of the regeneration of the dentin-pulp tissue is to restore the physiological functions of the pulp such as sensibility, the ability to repair by mineralization and pulp immunity.²⁸

There are 2 types of pulp capping, namely direct pulp capping and indirect pulp capping.²⁹Direct pulp capping (DPC) is a primary dental treatment indicated after minor mechanical exposures of less than 1 mm.³⁰DPC is performed on mechanically exposed healthy pulp by applying a biocompatible material to prevent leakage of bacteria and toxins in the exposed area while maintaining vitality and accelerating pulp healing.^31-33Indications for DPC include minimal exposure of pulp and minimal bleeding in exposed pulp areas. Contraindications for DPC include pathological pulp conditions based on radiographs, a history of spontaneous pain, and bleeding in the pulp area.³⁴

Indirect pulp capping (IPC) was performed on caries lesions that had approached the pulp chamber. The IPC method was carried out by removing all caries tissue except caries dentin with a soft consistency using an excavator to support the formation of reactionary dentine as a reaction from odontoblast cells which is considered as a physiological process. The process is continued by closing the cavity using biocompatible materials.³² Indications for IPC are deep caries lesions near the pulp tissue, no tooth mobility, no history of spontaneous pain, no pathological conditions in the pulp, and no alveolar bone resorption on radiographs. IPC contraindications include pathological pulp conditions based on radiographs, a history of spontaneous pain, mobility in the teeth, and alveolar bone resorption based on radiographic examination.^34,35

Proanthocyanidin:

Proanthocyanidin (PA) is a natural flavonoid from the condensation of tannins contained in grape seeds (Vitis spp.) of 35.3 mg/g and as antioxidant, immunomodulatory, anti-bacterial, antiviral, anti-inflammatory, anti-allergy, and vasodilator agent.^36-38The application of PA to the pulp facilitates increased expression and cross linking of dentin Collagen Type 1 A (COL1A1) and is biocompatible with the pulp. The expression of biomineralization, differentiating odontogenic regulators such as Runt-related transcription factor 2 (RUNX2), Bone Morphogenic Protein-2 (BMP2), Osteocalcin (OCN), and Dentin Sialophosphoprotein (DSPP).^39-41 Matrix deposition and biomineralization play an important role in the formation of new dentin. The exposed dental pulp cells treated natural biomaterial showed increased proliferation and expression of the genes required for extracellular matrix (ECM) formation.^42,43

PA was obtained by extracting grape seed (Vitis vinifera) using ionic liquid as much as 0.2g of dried grape seed weighed in an extraction tube 15mL and 5mL IL added. The samples were processed in the vortex for 10 s and placed in a shaker for 4h of extraction, at room temperature. After that, the samples were centrifuged for 15 minutes at 5000rpm and the supernatant was obtained from the filtration process. The samples obtained after extraction will be analyzed by High Performance Liquid Chromatography (HPLC) and Thin Layer Chromatography (TLC) to identify PA compounds.⁴⁴

Polyamidoamine:

Polyamidoamine (PAMAM) is a drug carrier of nano polymer composition capable of inducing tooth remineralization by absorbing Ca, P, and collagen matrix.⁴⁵ PAMAM is biocompatible, low toxicity, and immunomodulator.⁴⁶ PAMAM can attract Ca and P ions to induce remineralization. PAMAM is a macromolecular compound that can assist the regeneration of dentin. Immersion test in lactic acid for 14 days on control dentine showed demineralization and dentin with PAMAM administration showed that there was a decrease in demineralization in dentin. This is because the PAMAM macromolecules applied to demineralized dentin are able to bond Ca and P ions to form minerals in demineralized dentine so that remineralization occurs.⁴⁷

The PAMAM synthesis method is carried out by preparing the nucleus of the initiator molecule which contains a functional group that can react as an active site in the initial reaction. The growth of the outer layer of PAMAM is accomplished by adding the amine-terminated surface to the methyl acrylate resulting in an ester-terminated outer layer and bonding with ethylene diamine to obtain a new amino-terminated surface. The ester-terminated (half generation) synthesis of PAMAM dendrimers was carried out using ethylene diamine which was dissolved in methanol then mixed and put in a refrigerator. Then a drop of methyl acrylate is added to the dendrimer solution. The resulting mixture was then stored at room temperature for several days at 45℃. The solution will then turn pale yellow and form the solid particles. The synthesis stage of the amino-terminated (complete generation) PAMAM dendrimers was obtained by dissolving ethylene diamine and multi-esters in methanol separately. The multi-ester solution is then cooled and gradually added to the ethylene diamine solution. The resulting mixture is then stored at room temperature for several days until a clear solution is obtained.⁴⁸

Calcium Phosphate Nanoparticles:

Calcium phosphate (CP) nanoparticles are adhesive drug carriers with the ability to penetrate into the dentinal tubules.⁴⁹ CP nanoparticles release Ca and P ions and are able to neutralize acids quickly.^50,51 CP nanoparticles can induce remineralization and regeneration of dentin in pre-demineralization towards healthy dentin, neutralizes pH and can reduce biofilm production by bacteria.^15,52 CP nanoparticles have high bioactivity and cell adhesion and are biodegradable.²⁵CP nanoparticles are synthesized through spray-drying techniques. Calcium carbonate and dicalcium phosphate solutions were dissolved into acetic acid solution to obtain Ca and P ion concentrations of 8 and 5.333mmol/L. The solution is then sprayed into a heated chamber to evaporate distilled water and volatile acid. The dry particles collected by electrostatic precipitators produced CP nanoparticles with an average particle size of 116 nm.¹⁵

Pa Loaded Pamam-Cp Nanoparticles as Pulp Capping:

Pathogenesis of dental caries is correlated with S. wiggsiae and S. mutans colonization during the early stages of eruption.^9,53 Active caries is able to reach superficial zone and subsuperficial porosity was proven to induce demineralization process. The progressivity of the disease is stimulated by biofilm formation followed by sclerotic dentin formation. Bacterial colonization produces an exopolymer matrix that plays an important role as the environment of bacterial growth manifests in increasing the caries lesions. Bacteria diffuse into the dentinal tubule then invade the coronal dentin area and expand to the pulp.³² The manifestation of caries lesion is an opened cavity which needs to be treated with indirect pulp capping when it reaches the pulp chamber.

The most common material for dental pulp capping is calcium hydroxide (CH) which is able to induce remineralization by activating ATPase enzyme to stimulate reparative dentin formation, acts as bactericidal agent and neutralise acid from hydrogen ion from cement.³⁴ Despite its advantages, CH has high solubility after application within 1-2 years. This later would manifest in the formation of tunnel defect below the restoration which is able to increase the probability of secondary infection and microleakage in the pulp area, so the secondary infection could occur persistently then induce pulp necrotizing process. This condition could reduce the clinical success of pulp capping treatment.⁵⁴

A non-toxic natural biomaterial that induces dentin regeneration is a combination of PA and PAMAM-CP nanoparticles. This combination is able to increase dentin mineralisation, anticariogenic, and consistently neutralise pH.⁵⁵ The pH neutralise ability of this combination potentially suppresses nanoleakage risk due to bacterial metabolism, enzyme, and oral cavity liquid. Besides, the nano-sized PA and PAMAM-CP is able to penetrate into the dentinal tubule. Dentinal bonding with PA and PAMAM-CP nanoparticles through electrostatic interaction as the primary component of remineralization in an oral fluid-flowing environment. This condition could increase adhesive property between dentin and materials also high seal adaptation to regenerate dentin tissue which is able to increase the success of pulp capping.⁴⁷

Combination of PA loaded PAMAM-CP nanoparticles would be encapsulated releasing PA. PA suppresses macrophages activation and increases miR-506 expression so Toll Like Receptor-4 (TLR4) signalling pathway activation is inhibited. TLR4 signalling pathway is activated by lipopolysaccharide (LPS) from bacteria found in pulpitis and profunda caries. The blockage of this pathway suppresses MyD88, NOD2, Rip2 expression then disrupts the activation of caspase-1 and NF-kB signalling pathway manifest in decrease in Interleukin (IL) IL-1β/6, Tumor Necrosis Factor-α (TNF-α), p53, and p21 expression. This condition followed by disruption of cathepsin B and K and suppression of MMP-2/9 expression so the destruction process of the dentin and pulp is inhibited.^56-68

PA induces COL1A1 formation and cross-linking to dentin. COL1A1 is an organic material of dentin matrix. The cross-linking and density of COL1A1 was increased by adding the dose and reaching the highest point in 15% PA. Induction of COL1A1 expression is a manifestation of BMP-2 expression then activates the ERK1/2-Smad2/3/4 signaling pathway so importin 7 (IPO7) is elevated. IPO7 later induces HtrA1 expression manifests in Transforming Growth Factor-β1 (TGF-β1) expression. TGF-β1 is a growth factor that plays an important role in odontogenic differentiation and cell proliferation. TGF-β1 induces COL1A1 and Tissue Inhibitor Metalloproteinase-2 (TIMP-2) so the formation of dentin matrix is increased. This process followed by angiogenesis induction after Vascular Endothelial Growth Factor (VEGF) and Fibroblast Growth Factor-2 (FGF-2) expression through TGF-β1 expression facilitate nutrition and oxygen supply then increase the cell proliferation rate as the marker of optimum regeneration of dentin and pulp. The expression of TGF-β1 and activation of H19/SAHH signalling pathway could induce the expression of OCN, RUNX2, and Distal-Less Homeobox 3 (DLX3) then DSPP is elevated.^69-79 DSPP followed by release of calcium (Ca²⁺) and phosphate (PO₄^3-) by PAMAM-CP nanoparticles fragment facilitate PAMAM fixation to the ions to form hydroxyapatite. The increase in extracellular Ca²⁺ induces the formation of Dentin matrix protein 1 and its receptor, Glucose regulated protein-78 (DMP1-GRP78) complex and FGF2 expression, then induces interaction between Calcium release-activated calcium channel protein 1(Orai1) and stromal interaction molecule-1 (STIM1) to activate the store-operated Ca 2+ entry (SOCE) signaling pathway. This followed by Runx2 expression then induce Osterix (OSX), Wnt3a. RUNX2 expression manifests in odontoblast and odontoblast-like cell differentiation also increase dentinal tubule calcification.^80-89 Combination of PA and PAMAM-CP nanoparticles as pulp capping biomaterial is able to inhibit caries progression, neutralize acidic condition from biofilm, and strengthen the tooth structure.⁴⁷

CONCLUSION:

Based on our narrative review, combination of PA and PAMAM-CP nanoparticles may potential and beneficial as pulp capping biomaterial for dentin regeneration in dental caries. Further research is needed regarding the combination of proanthocyanidin and polyamidoamine-calcium phosphate nanoparticles as pulp capping biomaterials in regenerating dentin tissue.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Publication Center, Faculty of Dental Medicine, Universitas Airlangga for the facilities and support.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Suganya M. Soondron Y. Mahadeva-Rao US. Oral and Dietary Habits, and Immunological and Clinical Impacts on the Incidence of Dental Caries – A Review. Research J. Pharm. and Tech. 7(11):1348-1353.

2. Meyer F. Enax J. Early Childhood Caries: Epidemiology, Aetiology, and Prevention. International Journal of Dentistry 2018;1-7. DOI.10.1155/2018/1415873

3. Gayathri M. Light Microscopic Changes in Pulp due to Dental Caries at Different Stages. Research J. Pharm. and Tech. 2015;8(7):935-936. DOI: 10.5958/0974-360X.2015.00156.0

4. Rezvi FB. Abilasha R. Breast and Bottle Feeding as Risk Factors for Dental Caries - Review. Research J. Pharm. and Tech 2016; 9(9):1508-1512. doi: 10.1371/journal.pone.0142922. eCollection 2015.

5. Subasree S. Geetha RV. Essential oils in prevention of Dental Caries - An In-Vitro study. Research J. Pharm. and Tech. 2015;8(7): 909-911. DOI: 10.5958/0974-360X.2015.00148.1

6. Jain MR. Sethu G. Dental Caries and Obesity in Children of Age Groups 5-9 Years: A Preliminary Study. Research J. Pharm. and Tech. 2015;8(10):1353-1356. DOI: 10.5958/0974-360X.2015.00242.5

7. FDI World Dental Federation. Promoting oral health through fluoride: Adopted by the FDI general assembly: August 2017. Madrid, Spain. Int. Dent. J. 2018;68: 16–17. DOI: 10.1111/idj.12372

8. World Health Organization. Ending Childhood Dental Caries. Ending childhood dental caries: WHO implementation manual. World Health Organization. 2017;3.

9. Kameda M. Abiko Y. Washio J. Tanner A. Kressirer C. Mizoguchi I. Sugar Metabolism of Scardovia wiggsiae, A Novel Caries-Associated Bacterium. Frontiers in Microbiology. 2020;11. DOI: 10.3389/fmicb.2020.00479

10. Maganti A. Goothy SSK. Goothy S. Penumatsa GS. Manyam R. Association of Dental caries with difference in Leucocyte count. Research J. Pharm. and Tech 2020; 13(2):621-623. DOI: 10.5958/0974-360X.2020.00117.1

11. Fejerskov O. Nyvad B. Kidd E. Dental Caries: The Disease and Its Clinical Management. 3^rd ed. Oxford: Wiley Blackwell. 2015; 49-81.

12. Rohini SV. Kumar J. Incidence of dental caries and pericoronitis associated with impacted mandibular third molar – A radiographic study. Research J. Pharm. and Tech. 2017; 10(4): 1081-1084. DOI: 10.5958/0974-360X.2017.00196.2

13. Murthykumar K. The Impact of mushroom, chicory extracts, fresh fruits, xylitol containing chewing gums and milk products on dental caries-A Review. Research J. Pharm. and Tech. 2014;7(2): 266-268.

14. Delimont NM. Carlson BN. Prevention of dental caries by grape seed extract supplementation: A systematic review. Nutrition and Health. 2019; 1-10. doi: 10.1177/0260106019887890.

15. Liang K. Wang S. Tao S. Xiao S. Zhou H. Wang P. Cheng L. Zhou X. Weir M. Oates T. Li J. Xu H. Dental remineralization via poly(amidoamine) and restorative materials containing calcium phosphate nanoparticles. International Journal of Oral Science. 2019; 11(15):1-11. DOI: 10.1038/s41368-019-0048-z

16. Fusayama T. New Concepts in Operative Dentistry: Differentiating Two Layers of Carious Dentin and Using an Adhesive Resin. Chicago: Quintessence, 1980:13–59.

17. Nugraha AP. Mensana MP. Soebadi B. Husada D. Triyono EA. Prasetyo RA. Ernawati DS. Correlation of Low CD4+ Counts with High Dental Caries Prevalence in Children Living with Perinatal HIV/AIDS Undergoing Antiretroviral Therapy. Pesquisa Brasileira em Odontopediatria e Clínica Integrada 2019; 19(e4819):1-7. https://doi.org/10.4034/PBOCI.2019.191.119

18. Nugraha AP. Ernawati DS. Harijanti K. Parmadiati EA. Psychological Stress Induced Xerostomia and Hyposalivation: The Case Study in Indonesian Female Patient. J Int Dent Med Res 2019; 12(1): 216-219

19. Singh H. Essentials of Preclinical Conservative Dentistry, 2^nd ed. Wolters Kluwer. 2020;29-31.

20. Preedy VR. Watson RR. Nuts and Seeds in Health and Disease Prevention, 2^nd ed. Elsevier. 2020;117.

21. Koch G. Poulsen S. Espelid I. Haubek D. Pediatric Dentistry: A Clinical Approach, 3rd ed. Wiley Blackwell. 2017;102.

22. Lueckel H. Sebastian P. Kim R. Caries Management-Science and Clinical Practice. 2013;24-26.

23. Garrocho‐Rangel A. Esparza‐Villalpando V. Pozos‐Guillen A. Outcomes of direct pulp capping in vital primary teeth with cariously and non‐cariously exposed pulp: A systematic review. International Journal of Pediatric Dentistry. 2020;30(5):536-546. doi: 10.1111/ipd.12633.

24. Annusavice K. Chiayi S. Ralph R. Phillips’ science of dental materials. 12^th ed. Chicago: Elsevier. 2013, 308.

25. Iafisco M. Degli-Esposti L. Ramírez-Rodríguez G. Carella F. Gómez-Morales J. Ionescu. Fluoride-doped amorphous calcium phosphate nanoparticles as a promising biomimetic material for dental remineralization. Scientific Reports. 2018;8(1):5. doi: 10.1038/s41598-018-35258-x.

26. Suciadi SP. Nugraha AP. Ernawati DS. Ayuningtyas NF. Narmada IB. Prahasanti C. Dinaryanti A. Ihsan IS. Hendrinto E. Susilowati H. Rantam FA. The Efficacy of Human Dental Pulp Stem Cells in regenerating Submandibular Gland Defects in Diabetic Wistar Rats (Rattus novergicus). Research J. Pharm. and Tech. 2019; 12(4):1573-1579. DOI: 10.5958/0974-360X.2019.00261.0

27. Dhar V. Marghalani AA. Crystal YO. Use of vital pulp therapies in primary teeth with deep caries lesions. Pediatr Dent 2017;39(5):E146-E159.

28. Sismanoglu S. Ercal P. Dentin-Pulp Tissue Regeneration Approaches in Dentistry: An Overview and Current Trends. In: Turksen K. (eds) Cell Biology and Translational Medicine, Springer, Cham.: Advances in Experimental Medicine and Biology 2020;133-148. DOI: 10.1007/5584_2020_578

29. Cannon L. Bioactive Material Considerations for Vital Pulp-Capping Protocols. 2nd ed. Dental Learning Systems, LLC; 2017, 3-10.

30. Sujlana A. Pannu P. Direct pulp capping: A treatment option in primary teeth? Pediatric Dental Journal. 2017;1-2. DOI 10.1016/j.pdj.2016.10.001

31. Mostafa D. Bayoumi FS. Taher HM. Abdelmonem BH. Eissa TF. Antimicrobial potential of Mentha Spp. essential oils as raw and loaded solid lipid nanoparticles against dental caries. Research J. Pharm. and Tech. 2020; 13(9):4415-4422. DOI: 10.5958/0974-360X.2020.00781.7

32. Goldberg M. Indirect and Direct Pulp Capping: Reactionary vs. Reparative Dentins. JSM Dentistry. 2020;8(1):1119.

33. Shenoy A. Mala K. Endodontics Principles & Practice. Elsevier. 2016,217.

34. Garg N. Amit G. Textbook of Operative Dentistry. 2^nd ed. New Delhi: Jaypee. 2013, 256-257.

35. Torabinejad M. Walton R. Fouad A. Endodontics Principles and Practice, 5th ed. Elsevier Saunders. 2014, 28.

36. Sullivan I. Proanthocyanidins: Food Sources, Antioxidant Properties and Health Benefits. Food and Beverage Consumption and Health; 2015, 186.

37. Bladé C. Arola-Arnal A. Crescenti A. Suárez MI. Bravo F. Aragonès G. Proanthocyanidins and Epigenetics. In: Patel V., Preedy V.(eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. 2017, 1-24.

38. Alhasyimi AA. Rosyida NF. Rihadini MS. Postorthodontic Relapse Prevention by Administration of Grape Seed (Vitis vinifera) Extract Containing Cyanidine in Rats. Eur J Dent. 2019;13(4):629-634. doi: 10.1055/s-0039-3401440.

39. Nugraha AP. Narmada IB. Ernawati DS. Dinaryanti A. Hendrianto E. Ihsan IS. Riawan W. Rantam FA. Osteogenic potential of gingival stromal progenitor cells cultured in platelet rich fibrin is predicted by core-binding factor subunit-α1/Sox9 expression ratio (in vitro). F1000Research 2018, 7:1134. doi: 10.12688/f1000research.15423.1.

40. Nugraha AP. Narmada IB. Ernawati DS. Dinaryanti A. Hendrianto E. Ihsan IS. Riawan W. Rantam FA. In vitro bone sialoprotein-I expression in combined gingival stromal progenitor cells and platelet rich fibrin during osteogenic differentiation. Tropical Journal of Pharmaceutical Research December 2018; 17 (12): 2341-2345. DOI: 10.4314/tjpr.v17i12.4

41. Nugraha AP. Narmada IB. Ernawati DS. Dinaryanti A. Hendrianto E. Ihsan IS. Riawan W. Rantam FA. Bone alkaline phosphatase and osteocalcin expression of rat’s Gingival mesenchymal stem cells cultured in platelet-rich fibrin for bone remodeling (in vitro study). Eur J Dent 2018;12:566-7 doi: 10.4103/ejd.ejd_261_18.

42. Prahasanti C. Nugraha AP. Saskianti T. Suardita K. Riawan W. Ernawati DS. Exfoliated Human Deciduous Tooth Stem Cells Incorporating Carbonate Apatite Scaffold Enhance BMP-2, BMP-7 and Attenuate MMP-8 Expression During Initial Alveolar Bone Remodeling in Wistar Rats (Rattus norvegicus). Clinical, Cosmetic and Investigational Dentistry 2020:12 79–85. doi: 10.2147/CCIDE.S245678.

43. Saskianti T. Nugraha AP. Prahasanti C. Ernawati DS. Suardita K. Riawan W. Immunohistochemical analysis of stem cells from human exfoliated deciduous teeth seeded in carbonate apatite scaffold for the alveolar bone defect in Wistar rats ( Rattus novergicus). F1000Res. 2020;22(9):1164. doi: 10.12688/f1000research.25009.2.

44. Chen H. Gu L. Liao B. Zhou X. Cheng L. Ren B. Advances of Anti-Caries Nanomaterials. Molecules. 2020;25(21):5047. doi: 10.3390/molecules25215047.

45. Liang K. Xiao S. Weir M. Bao C. Liu H. Cheng L. Poly(amido amine) dendrimer and dental adhesive with calcium phosphate nanoparticles remineralized dentin in lactic acid. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2017;106(6):2414-2424. doi: 10.1002/jbm.b.34050.

46. Das I. Borah J. Sarma D. Hazarika S. Synthesis of PAMAM dendrimer and its derivative PAMOL: Determination of thermophysical properties by DFT. Journal of Macromolecular Science Part A. 2018;1–8. https://doi.org/10.1080/10601325.2018.1481345

47. Ben-Nissan B. Advances in Calcium Phosphate Biomaterials. 2nd ed. Verlag Berlin Heidelberg: Springer; 2014, 511.

48. De Groot K. Bioceramics Calcium Phosphate. 1st ed. CRC Press; 2018, 226.

49. Heimann BR. Calcium Phosphate: Structure, Synthesis, Properties, and Applications. 1st ed. Germany: NOVA Biomechanic; 2012, 509.

50. Tao S. He L. Xu H. Weir M. Fan M. Yu Z. Dentin remineralization via adhesive containing amorphous calcium phosphate nanoparticles in a biofilm-challenged environment. Journal of Dentistry. 2019; 89:103193. doi: 10.1016/j.jdent.2019.103193.

51. National Health Society. Prevention and Management of Dental Caries in Children. Scotland: Scottish Dental Clinical Effectiveness Programme. 2018:21.

52. Song M. Yu B. Kim S. Hayashi M. Smith C. Sohn S. Clinical and Molecular Perspectives of Reparative Dentin Formation. Dental Clinics of North America. 2017;61(1):93-110. doi: 10.1016/j.cden.2016.08.008.

53. Delimont N. Carlson B. Prevention of dental caries by grape seed extract supplementation: A systematic review. Nutrition and Health. 2019;26(1):43-52. doi: 10.1177/0260106019887890.

54. Cooper P. Chicca I. Holder M. Milward M. Inflammation and Regeneration in the Dentin-pulp Complex: Net Gain or Net Loss? 2017;43(9S):S87-89. doi: 10.1016/j.joen.2017.06.011.

55. Lee J. Kim Y. Kim Y. Choi M. Min S. Joo Y. Grape seed proanthocyanidin inhibits inflammatory responses in hepatic stellate cells by modulating the MAPK, Akt and NF-κB signaling pathways. International Journal of Molecular Medicine. 2017;40(1):226-234. doi: 10.3892/ijmm.2017.2997.

56. Leme-Kraus A. Aydin B. Vidal C. Phansalkar R. Nam J. McAlpine J. Biostability of the Proanthocyanidins-Dentin Complex and Adhesion Studies. Journal of Dental Research. 2017;96(4):406-412. doi: 10.1177/0022034516680586.

57. Nam J. Phansalkar R. Lankin D. McAlpine J. Leme-Kraus A. Vidal C. Absolute Configuration of Native Oligomeric Proanthocyanidins with Dentin Biomodification Potency. The Journal of Organic Chemistry. 2017;82(3):1316-1329. doi: 10.1021/acs.joc.6b02161.

58. Balalaie A. Rezvani M. Mohammadi B. Dual function of proanthocyanidins as both MMP inhibitor and crosslinker in dentin biomodification: A literature review. Dental Materials Journal. 2018;37(2):173-182. doi: 10.4012/dmj.2017-062.

59. Feng G. Zheng K. Cao T. Zhang J. Lian M. Huang D. Repeated stimulation by LPS promotes the senescence of DPSCs via TLR4/MyD88-NF-κB-p53/p21 signaling. Cytotechnology. 2018;70(3):1023-1035. doi: 10.1007/s10616-017-0180-6.

60. Yumoto H. Hirao K. Hosokawa Y. Kuramoto H. Takegawa D. Nakanishi T. The roles of odontoblasts in dental pulp innate immunity. Japanese Dental Science Review. 2018;54(3):105-117. doi: 10.1016/j.jdsr.2018.03.001.

61. Atabek Ş. Özden A. Comparison of the Effect of Proanthocyanidin Surface Treatments on Shear Bond Strength of Different Cements. Materials. 2019;12(17):2676. doi: 10.3390/ma12172676.

62. El-Sayed FK. Elsalawy R. Ibrahim N. Gadalla M. Albargasy H. Zahra N. The Dental Pulp Stem/Progenitor Cells-Mediated Inflammatory-Regenerative Axis. Tissue Engineering Part B: Reviews. 2019;25(5):445-460. doi: 10.1089/ten.TEB.2019.0106.

63. Wang J. Du Y. Deng J. Wang X. Long F. He J. MicroRNA-506 Is Involved in Regulation of the Occurrence of Lipopolysaccharides (LPS)-Induced Pulpitis by Sirtuin 1 (SIRT1). Medical Science Monitor. 2019;25:10008-10015. doi: 10.12659/MSM.918172.

64. Jafari R. Karamzadeh R. Pesaran HF. Sayyadizadeh F, Chekini Z. Aghajanpour S. Human closed and open apex premolar teeth express different toll‐like receptor. Molecular Genetics & Genomic Medicine. 2020;8(7):2. doi: 10.1002/mgg3.1268.

65. Kwak S. Cheon Y. Lee C. Jun H. Yoon K. Lee M. Grape Seed Proanthocyanidin Extract Prevents Bone Loss via Regulation of Osteoclast Differentiation, Apoptosis, and Proliferation. Nutrients. 2020;12(10):3164. doi: 10.3390/nu12103164.

66. Firouzmandi M. Vasei F. Giti R. Sadeghi H. Effect of silver diamine fluoride and proanthocyanidin on resistance of carious dentin to acid challenges. PLoS ONE. 2020;15(9):e0238590. doi: 10.1371/journal.pone.0238590.

67. Hashemi-Beni B. Khoroushi M. Foroughi M. Karbasi S. Khademi A. Tissue engineering: Dentin – pulp complex regeneration approaches (A review). Tissue Cell 2017;49(5):552-564. doi: 10.1016/j.tice.2017.07.002.

68. Jeanneau C. Lundy F. El Karim I. About I. Potential Therapeutic Strategy of Targeting Pulp Fibroblasts in Dentin-Pulp Regeneration. J Endod. 2017;43(9S): S17-S24. doi: 10.1016/j.joen.2017.06.007.

69. Lin X. Xie F. Ma X. Hao Y. Qin H. Long J. Fabrication and characterization of dendrimer-functionalized nano-hydroxyapatite and its application in dentin tubule occlusion. J Biomater Sci Polym Ed. 2017;28(9):846-863. doi: 10.1080/09205063.2017.1308654.

70. Jani P. Liu C. Zhang H. Younes K. Benson M. Qin C. The role of bone morphogenetic proteins 2 and 4 in mouse dentinogenesis. Archives of Oral Biology. 2018;90:33-39. doi: 10.1016/j.archoralbio.2018.02.004.

71. Kanaya S. Xiao B. Sakisaka Y. Suto M. Maruyama K. Saito M. Extracellular calcium increases fibroblast growth factor 2 gene expression via extracellular signal-regulated kinase 1/2 and protein kinase A signaling in mouse dental papilla cells. 2018;26:e20170231. doi: 10.1590/1678-7757-2017-0231.

72. Li X. Ban G. Al-Shameri B. He X. Liang D. Chen W. High-temperature Requirement Protein A1 Regulates Odontoblastic Differentiation of Dental Pulp Cells via the Transforming Growth Factor Beta 1/Smad Signaling Pathway. Journal of Endodontics. 2018;44(5):765-772.J doi: 10.1016/j.joen.2018.02.003. Epub 2018 Mar 24.

73. Zeng L. Sun S. Han D. Liu Y. Liu H. Feng H. Long non-coding RNA H19/SAHH axis epigenetically regulates odontogenic differentiation of human dental pulp stem cells. Cellular Signalling. 2018;52:65-73. doi: 10.1016/j.cellsig.2018.08.015.

74. Zeng L. Zhao N. Li F. Han D. Liu Y. Liu H. miR-675 promotes odontogenic differentiation of human dental pulp cells by epigenetic regulation of DLX3. Experimental Cell Research. 2018;367(1):104-111.

75. Chen J. Liao L. Lan T. Zhang Z. Gai K. Huang Y. Treated dentin matrix‐based scaffolds carrying TGF-β1/BMP4 for functional bio-root regeneration. Applied Materials Today. 2020;20:100742. doi: 10.1016/j.yexcr.2018.03.035.

76. Nawrot-Hadzik I. Matkowski A. Kubasiewicz-Ross P. Hadzik J. Proanthocyanidins and Flavan-3-ols in the Prevention and Treatment of Periodontitis—Immunomodulatory Effects, Animal and Clinical Studies. Nutrients. 2021;13(1):239. doi: 10.3390/nu13010239.

77. Zhang Y. Zhang H. Yuan G. Yang G. Effects of transforming growth factor-β1 on odontoblastic differentiation in dental papilla cells is determined by IPO7 expression level. Biochemical and Biophysical Research Communications. 2021;545:105-111. doi: 10.1016/j.bbrc.2021.01.076.

78. Lin P. Chang H. Yeh C. Chang M. Chan C. Kuo H. Transforming growth factor beta 1 increases collagen content, and stimulates procollagen I and tissue inhibitor of metalloproteinase-1 production of dental pulp cells: Role of MEK/ERK and activin receptor-like kinase-5/Smad signaling. Forrmos Med Assoc 2017;116(5):351-358. doi: 10.1016/j.jfma.2016.07.014.

79. Ahmad A. Kaewpungsup P. Khorattanakulchai N. Rattanapisit K. Pavasant P. Phoolcharoen W. Recombinant human dentin matrix protein 1 (DMP1) induces the osteogenic differentiation of human periodontal ligament cells. Biotechnology Reports. 2019;23:e00348. doi: 10.1016/j.btre.2019.e00348. eCollection 2019 Sep.

80. Bae J. Son W. Yoo K. Yoon S. Bae M. Lee D. Effects of Poly(Amidoamine) Dendrimer-Coated Mesoporous Bioactive Glass Nanoparticles on Dentin Remineralization. Nanomaterials. 2019;9(4):591. doi: 10.3390/nano9040591.

81. Osmond M. Mizenko R. Krebs M. Rapidly Curing Chitosan Calcium Phosphate Composites as Dental Pulp Capping Agents. Regenerative Medicine Frontiers. 2019;1:e190002. https://doi.org/10.20900/rmf20190002

82. Saito K. Nakatomi M. Ohshima H. Dentin Matrix Protein 1 Compensates for Lack of Osteopontin in Regulating Odontoblast like Cell Differentiation after Tooth Injury in Mice. Journal of Endodontics. 2019;46(1):89-96. doi: 10.1016/j.joen.2019.10.002.

83. Wu Q. Shan T. Zhao M. Mai S. Gu L. The inhibitory effect of carboxyl-terminated polyamidoamine dendrimers on dentine host-derived matrix metalloproteinases in vitro in an etch-and-rinse adhesive system. R. Soc. open sci. 2019;6:182104. doi: 10.1098/rsos.182104.

84. Howard J. Gardner L. Saifee Z. Geleil A. Nelson I. Colombo J. Synthesis and characterization of novel calcium phosphate glass-derived cements for vital pulp therapy. Journal of Materials Science: Materials in Medicine. 2020;31(1):9-10. doi: 10.1007/s10856-019-6352-5.

85. Zhu N. Wang D. Xie F. Qin M. Lin Z. Wang Y. Fabrication and Characterization of Calcium-Phosphate Lipid System for Potential Dental Application. Frontiers in Chemistry. 2020;8:161. doi: 10.3389/fchem.2020.00161

86. Chen Y. Koshy R. Guirado E. George A. STIM1 a calcium sensor promotes the assembly of an ECM that contains Extracellular vesicles and factors that modulate mineralization. Acta Biomaterialia. 2021;120:224-239. doi: 10.1016/j.actbio.2020.10.011.

87. Gallorini M. Krifka S. Widbiller M. Schröder A. Brochhausen C. Cataldi A. Distinguished properties of cells isolated from the dentin-pulp interface. Annals of Anatomy - Anatomischer Anzeiger. 2021;234:151628. doi: 10.1016/j.aanat.2020.151628

88. Liu C. He H. Developments and Applications of Calcium Phosphate Bone Cements. Springer Series in Biomaterials Science and Engineering; 2018;3-10.

89. Sergey A. Ben-Nissan B. Conway R. Macha I. Advances in Calcium Phosphate Biomaterials. 1st ed. Heidelberg New York Dordrecht London: Springer; 2014, 485-511.

Received on 09.05.2021 Modified on 18.08.2021

Research J. Pharm. and Tech. 2022; 15(7):2888-2894.

DOI: 10.52711/0974-360X.2022.00482