valenciana_solis_et

INTRODUCTION

Chitosan is a product of the deacetylation of chitin, which is a polysaccharide that is widely distributed in nature, mainly in the exoskeleton of crustaceans. Chitosan has been approved as safe for use by the United States Food and Drug Administration (FDA) because of its biocompatibility, biodegradability, non-toxicity, and ability to adhere to the mucosa (1). Given its specific physicochemical and biological characteristics, chitosan is used in the food, medical, cosmetics, water treatment, metal extraction and recycling industries (2) and also biomedicine. Chitosan has bactericidal, antibacterial, antiviral, and antitumor characteristics, and has been studied for applications in biomedical sciences (3).

Development in biomedical sciences and technology is increasing, and the study of new compounds is a priority in the production of treatment alternatives for various ailments and diseases. In biomedicine, the development of nanotechnological materials-nanomaterials such as nanoparticles, microspheres, micelles and hydrogels-has been trending (4).

The production and use of biodegradable polymers is of great interest in the pharmaceutical industry and biomedical research. According to the “RAE”, a compound is biodegradable when it can be degraded by biological action (5). For biomedical use, biodegradable is the conversion of materials into less complex intermediate compounds or final products by means of solubilization, hydrolysis or biological action (6).

Historically, biodegradable hydrogels have had important applications in controlled-release drug delivery, the advantage of which is that they eliminate the need to remove “vestiges” or “leftovers” of these drugs (7). Hydrogels are a type of three-dimensional (3D) polymeric network that accumulates many water particles that present specific physicochemical properties to satisfy specific needs. For this reason, they have been applied in the biomedical field in studies of physiological and pathological mechanisms, disease therapies and tissue regeneration (8).

USE OF CHITOSAN HYDROGELS IN DENTISTRY

Chitosan has been studied in biomedicine and especially in dentistry because of its restorative properties and its potential for replacing or improving the functions of various tissues (9). Diseases of the oral cavity, such as dental caries, gingivitis, periodontitis and fungal and endodontic infections have multifactorial etiology, making the development of materials with a “multifunctional” approach important.

CHITOSAN IN REMINERALIZATION OF

DENTAL ENAMEL

The search for non-invasive treatments for the prevention and control of dental caries is of primary interest in dental research, since, because of its inorganic nature, the regeneration of tooth enamel is challenging (10). Tooth enamel is made up of 95% inorganic matrix, 1% to 2% organic matrix and 2% to 4% water and helps protect the vital tissues of the tooth (dentin and pulp) from environmental stimuli such as temperature and physical and chemical stimuli (11).

The positive charges of chitosan facilitate adherance to the enamel surface. In addition, tooth enamel has a negative charge, which improves adhesion. The ability of chitosan to penetrate the surface of the enamel and help remineralize the deeper layers of the enamel has been reported (12).

MATERIALS AND METHODS

To conduct this systematic review, we used the PRISMA guidelines and checklist for preferred reporting items for systematic reviews and meta-analyses (13).

SEARCH STRATEGY AND SELECTION OF STUDIES

A comprehensive literature search was conducted using the PubMed electronic database. The keywords used for the search were “Chitosan AND Hydrogel AND Dentistry,” finding a total of 119 articles related to these keywords.

For the articles to be reviewed in this article, the following inclusion criteria were established: time interval between 2018 and 2023; articles that contain chitosan-based hydrogels focused on the dental area; articles that contain chitosan-based hydrogels in combination with some other material; and original articles.

The exclusion criteria were articles published before 2018 and literature review articles, systematic reviews and meta-analyses (Figure 1).

RESULTS

According to the bibliographic review, various dental uses of chitosan were found, mainly on the remineralization of tooth enamel, osteogenesis, antimicrobial effect, tissue regeneration and in synergy with dental materials to increase the effect of dentin adhesives (9). For this review, only chitosan-based hydrogel formulations were considered.

Remineralizing effect

In the first study, a chitosan hydrogel was designed in combination with an amelogenin peptide derivative with the aim of creating a more clinically effective anticariogenic treatment characterized by affecting bacterial inhibition and promoting enamel remineralization. This research showed a reduction in biofilm adhesion of 95.43% and up to 100% in biofilm formation. Regarding enamel remineralization, it showed a recovery of surface microhardness of up to 50.06%, shallower carious lesions, and significantly less mineral loss (14).

Another study reported on a hydrogel based on chitosan and agarose to treat specimens demineralized by phosphoric acid. All specimens treated with the agarose hydrogel and agarose and chitosan showed improved microhardness values compared with that of acid-etched enamel. The main difference was between the treatments with the hydrogels at 7 days, since the treatment with the agarose hydrogel showed growth of the prism, while the specimen treated with chitosan-agarose showed an increase in the interprismatic zones (10) (Table 1).

Bone regeneration

For bone regeneration, a chitosan and poly(ethylene glycol) hydrogel was prepared in which acetylsalicylic acid was encapsulated to achieve a continuous and prolonged release for 14 days, promoting the proliferation of periodontal ligament stem cells and therefore osteogenic activity (17).

Another interesting article described the use of gum Arabic, chitosan and nanohydroxyapatite to create a hydrogel for bone regeneration. The hydrogel showed good resistance to compression, low allergic activity and good biodegradation when implanted subcutaneously in mice. These findings showed that hydrogel has broad possibilities for the elaboration of bioactive nanostructures to carry out tests in bone regeneration (18).

Anticariogenic potential effect

The development of polyfunctional hydrogels is an important part of the evolution of dental materials. Ren et al. developed a chitosan hydrogel loaded with peptide derived from amelogenin, with the aim of creating a dental biomaterial with a remineralizing effect and simultaneous antimicrobial effect, thereby developing a material with an anticariogenic effect. This hydrogel reduced the adhesion of biofilms by up to 95% and inhibited biofilm formation by up to 100%, providing an antimicrobial effect. With respect to the remineralization of enamel, it showed a recovery of microhardness by up to 50% (14) (Table 3).

Jaw bone infection is one of the most prevalent side effects after a dental extraction procedure that can lead to more serious processes such as osteomyelitis, osteoradionecrosis, and drug-related osteonecrosis (19) (Table 2).

Antimicrobial effect

The antimicrobial effects of chitosan are important. Because of its polycationic nature, electrostatic interactions occur between the chitosan and the anionic groups found on the surface of the bacterial cell, subsequently causing permeability of the bacterial membrane and, therefore, loss of their vital compounds, leading to cell death.

The combination of chitosan and zinc oxide exhibited a cytotoxic effect against S. mutans, but, also had more than 90% cell viability in human gingival fibroblasts; the combination of chitosan hydrogel and zinc oxide had better effectiveness than chitosan hydrogel, exhibiting an improvement of up to 33%, and zinc oxide of up to 45% (21).

Sublet and Popescu made a chitosan hydrogel in combination with poly (vinyl alcohol) (PVA) and silver nanoparticles. They reported that the chitosan/PVA hydrogels trapped with silver nanoparticles exhibited high inhibitory activity against S. aureus and K. pneumonia. Vitality tests confirmed the very low cytotoxicity of chitosan/PVA hydrogels with or without silver nanoparticles (22) (Table 4).

Periodontal treatment

The ability to regenerate tissues is another important characteristic of chitosan. Periodontal diseases are inflammatory processes in which destruction of the tissues that support the teeth, the bone, the periodontal ligament and the cementum occurs. Abboud et al. designed a chitosan hydrogel loaded with insulin for local administration in patients with periodontitis (23). Another study observed the synergistic effect of S. baicalinase’s radix extract and chitosan, which had an inhibitory effect against hyaluronidase and an inhibitory effect on the growth of pathogens (24).

A hydrogel loaded with lyophilized platelets was made with the ability to improve the viability of platelets, demonstrating that chitosan has the potential to serve as a vehicle for the administration of biological products such as growth factors (25) (Table 5).

Pulp therapy

Pulpal regeneration is one of the most important challenges for dentistry and for this reason, attention has been focused on chitosan which, due to its characteristics, is attractive for the development of new treatments. A chitosan hydrogel with vascular endothelial growth factor was studied to promote the odontogenic differentiation of pulp stem cells, and the results suggested that the hydrogel can continuously release vascular endothelial growth factor and contribute to odontogenic differentiation. Therefore, the hydrogel would be a perfect vehicle for bioactive molecules (26).

Another study investigated a chitosan hydrogel with fibrin, which helped decrease antigen-presenting cells, myeloid dendritic cells, T cells and B cells. NK cells decreased significantly in those treated with the fibrin-chitosan hydrogel compared with the control, indicating an improvement in the inflammatory response (27).

Moreira and Sarra created a chitosan hydrogel that, when applied with a blood clot and photomodulation therapy, induces the differentiation of pulp cells. This article provided information on improving the previous results of dental pulp regeneration through cell localization approaches (28). The creation of a chitosan hydrogel with fibroblast growth factor (bFGF-) to investigate its effects on angiogenic induction in human dental pulp stem cells was the objective of this research. The conclusions of this article show us that Poli scaffolds (ε-caprolactone)/chitosan (PCL/CS) loaded with fibroblast growth factor (bFGF-) have the potential to promote the angiogenesis of dental pulp stem cells (hDPSC), leading to new expectations for angiogenesis and a possible advance in regenerative endodontic procedures (29) (Table 6).

Other uses

The use of chitosan as a hydrogel has been reported in combined applications as having an antimicrobial and osteogenic effect, as in the case of this study, in which a hydrogel based on carboxymethyl-chitosan (CMCS) was created in combination with clindamycin (CDM), This hydrogel showed antimicrobial activity against streptococcus sanguinis for 14 days and had acceptable osteogenic activity, having cell viability with human mesenchymal stem cells (hMSCs) and inducing their mineralization (19).

The treatment of osteoradionecrosis is one of the most important challenges in dentistry. In this study, we created a hydrogel in which chitosan was used as a vehicle for the local administration of parathyroid hormone and which was more successful than existing treatments (30).

Another interesting study reported that a chitosan hydrogel in combination with penciclovir and lavender oil had better success than a commercial penciclovir gel for the treatment of cold sores, showing improved prolonged release, bioavailability and, therefore, improved effectiveness on the mucosa than commercial gel (31) (Table 7).

DISCUSSION

Scientific evidence has demonstrated that chitosan is a bionanomaterial with considerable potential in the biomedical sciences because it can be used as a vehicle for drug administration, tissue regeneration, and antibacterial effects (9). In the present review, 21 articles describing chitosan-based hydrogels for the dental field were analyzed.

Chitosan-based hydrogels have been shown to be an option for the remineralization of tooth enamel and provide novel anticariogenic treatments. For amelogenin-derived peptide hydrogel, a recovery of up to 50% in microhardness was shown in damaged tooth enamel (14). For chitosan hydrogel in combination with agarose, the enamel prism grew with a 7-day treatment (10).

Chitosan-based hydrogels provide active agents in bone regeneration in combination with artificial polymers. Chitosan and polyethylene glycol hydrogel was used as a capsule in which acetylsalicylic acid was introduced, which induced the proliferation of periodontal ligament stem cells and induced osteogenic activity (17). Another study used gum Arabic, chitosan and nanohydroxyapatite, which, because of its physical characteristics, has broader potential for the development of bioactive structures to make biomaterials for bone regeneration (18).

A hydrogel based on chitosan was found to have a remineralizing and antimicrobial effect and an anticariogenic effect. In this research, the authors made a chitosan hydrogel in combination with peptide derived from amelogenin, in which a reduction of biofilm adhesion on enamel of more than 95% and a 100% reduction in biofilm formation was reported (14).

Hydrogels with an antimicrobial effect have been developed, among which is a chitosan and zinc oxide hydrogel showing a cytotoxic effect against S. mutans and a 100% viability in human gingival fibroblasts (21). Another investigation was based on a hydrogel of chitosan/PVA/ and silver nanoparticles which exhibited inhibitory activity against S. aureus and K. pneumonia; low toxicity was also shown in viability tests (22).

Hydrogels have been reported to act as potential agents for the treatment of periodontal disease and pulp therapy since chitosan shows a potential tissue regeneration effect. In the first case, a hydrogel loaded with insulin was investigated for the treatment of periodontitis (23). Another study was based on the combination of S. baicalensis radix extract and chitosan, which had an inhibitory effect against hyaluronidase combined with an inhibitory effect on the growth of pathogens (24, 29).

In the case of pulp therapy, chitosan hydrogels were studied in combination with vascular endothelial growth factor, which contributes to odontogenic differentiation (26). Another study showed that a chitosan hydrogel in combination with fibrin improved the inflammatory response (27). A chitosan hydrogel was also combined with a blood clot and, with the help of photomodulatory therapy, induced the differentiation of pulp cells (28).

Other uses of chitosan hydrogels have also been found, for example, the combination of a chitosan hydrogel with clindamycin to obtain an antimicrobial and osteogenic effect (19). An alternative has also been sought in the treatment of osteoradionecrosis, in which chitosan hydrogel was combined with parathyroid hormone, revealing an improvement compared with existing treatments (30). The chitosan hydrogel in combination with penciclovir for the treatment of cold sores had a longer release and better bioavailability than the commercial chitosan gel (31).

CONCLUSION

The use of chitosan in biomedicine is a cutting-edge topic as it has potential for use in different areas. In this review, different uses of chitosan-based hydrogels in different areas of dentistry were identified. Chitosan hydrogels have different applications such as remineralization of tooth enamel, tissue regeneration, antimicrobial effects and, especially, as a vehicle for the administration of drugs. The most specific advantage of chitosan is its low cost and availability, since being a natural polymer it is found in nature and can be obtained in a straightforward way. The prospects for the use of this material are positive since the potential of this bionanomaterial is broad. Although more studies are needed in reference to the use of chitosan, either as an active ingredient or as a vehicle for drug administration, the scientific evidence shows us that it is a viable option.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHOR CONTRIBUTION STATEMENT

Conceptualization and design: J.A.V.S. and C.B.J.

Literature review: J.A.V.S. and C.B.J.

Methodology and validation: C.G.F. and C.B.J.

Formal analysis: C.G.F., L.A.A.G. and C.B.J.

Investigation and data collection: J.A.V.S. and C.B.J.

Resources: C.G.F., L.A.A.G. and C.B.J.

Data analysis and interpretation: J.A.V.S. and C.B.J.

Writing-original draft preparation: J.A.V.S.

Writing-review and editing: C.G.F., G.A.M.C., V.Z.A. and C.B.J.

Supervision: C.G.F., L.A.A.G., G.A.M.C., V.Z.A. and C.B.J.

Project administration: C.G.F. and C.B.J.

ACKNOWLEDGEMENTS

Jesús Antonio Valenciana-Solís wants to thank CONAHCYT for the scholarship to complete his postgraduate degree.

REFERENCES

1. Wang W., Meng Q., Li Q., Liu J., Zhou M., Jin Z., et al. Chitosan Derivatives and Their Application in Biomedicine. International Journal of Molecular Sciences. 2020; 21 (2): 487.

2. Ngo D.-H., Vo T.-S., Ngo D.-N., Kang K.-H., Je J.-Y., Pham H.N.-D., et al. Biological effects of chitosan and its derivatives. Food Hydrocolloids. 2015; 51: 200-16.

3. Zhao D., Yu S., Sun B., Gao S., Guo S., Zhao K. Biomedical Applications of Chitosan and Its Derivative Nanoparticles. Polymers. 2018; 10 (4):

4. Qin Y., Li P. Antimicrobial Chitosan Conjugates: Current Synthetic Strategies and Potential Applications. International Journal of Molecular Sciences. 2020; 21 (2): 499.

5. Royal Spanish Academy. Dictionary of the Spanish language [Internet]. Spain: Royal Spanish Academy; 2001. [Cited October 1, 2023]. Recovered from: https://www.rae.es/drae2001/biodegradable

6. Chandra R., Rustgi R. Biodegradable polymers. Progress in Polymer Science. 1998; 23 (7): 1273-335.

7. Kamath K.R., Park K. Biodegradable hydrogels in drug delivery. Advanced Drug Delivery Reviews. 1993; 11 (1-2): 59-84.

8. Cao H., Duan L., Zhang Y., Cao J., Zhang K. Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity. Signal Transduction and Targeted Therapy. 2021; 6 (1): 426.

9. Fakhri E., Eslami H., Maroufi P., Pakdel F., Taghizadeh S., Ganbarov K., et al. Chitosan biomaterials application in dentistry. International Journal of Biological Macromolecules. 2020; 162: 956-74.

10. Muşat V., Anghel E.M., Zaharia A., Atkinson I., Mocioiu O.C., Buşilă M., et al. A chitosan–agarose polysaccharide-based hydrogel for biomimetic remineralization of dental enamel. Biomolecules. 2021; 11 (8): 1137.

11. Lacruz R.S., Habelitz S., Wright J.T., Paine M.L. DENTAL ENAMEL FORMATION AND IMPLICATIONS FOR ORAL HEALTH AND DISEASE. Physiological Reviews. 2017; 97 (3): 939-93.

12. Arnaud T.M.S., de Barros Neto B., Diniz F.B. Chitosan effect on dental enamel de-remineralization: an in vitro evaluation. Journal of Dentistry. 2010; 38 (11): 848-52.

13. Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Medicine. 2009; 6 (7): e1000097.

14. Ren Q., Ding L., Li Z., Wang X., Wang K., Han S., et al. Chitosan hydrogel containing amelogenin-derived peptide: Inhibition of cariogenic bacteria and promotion of remineralization of initial caries lesions. Archives of Oral Biology. 2019; 100: 42-8.

15. Prajapati S., Ruan Q., Mukherjee K., Nutt S., Moradian-Oldak J. The Presence of MMP-20 Reinforces Biomimetic Enamel Regrowth. Journal of Dental Research. 2018; 97 (1): 84-90.

16. Zhang S., Zhao Y., Ding S., Zhou C., Li H., Li L. Facile Synthesis of In Situ Formable Alginate Composite Hydrogels with Ca (2+)-Induced Healing Ability. Tissue Engineering Part A. 2021; 27 (19-20): 1225-38.

17. Zhang Y., Dou X., Zhang L., Wang H., Zhang T., Bai R., et al. Facile fabrication of a biocompatible composite gel with sustained release of aspirin for bone regeneration. Bioact Mater. 2022; 11: 130-9.

18. Makar L.E., Nady N. Unmodified Gum Arabic/Chitosan/Nanohydroxyapatite Nanocomposite Hydrogels as Potential Scaffolds for Bone Regeneration. Polymers. 2022; 14 (15): 3052.

19. Sungkhaphan P., Thavornyutikarn B. Antibacterial and osteogenic activities of clindamycin-releasing mesoporous silica/carboxymethyl chitosan composite hydrogels. Royal Society Open Science. 2021; 8 (9): 210808.

20. Abdul-Monem M.M., Kamoun E.A., Ahmed D.M., El-Fakharany E.M., Al-Abbassy F.H., Aly H.M. Light-cured hyaluronic acid composite hydrogels using riboflavin as a photoinitiator for bone regeneration applications. Journal of Taibah University Medical Sciences. 2021; 16 (4): 529-39.

21. Afrasiabi S., Bahador A., Partoazar A. Combinatorial therapy of chitosan hydrogel-based zinc oxide nanocomposite attenuates the virulence of Streptococcus mutans. BMC Microbiology. 2021; 21 (1): 62.

22. Suflet D.M., Popescu I., et al. Dual Cross-Linked Chitosan/PVA Hydrogels Containing Silver Nanoparticles with Antimicrobial Properties. Pharmaceutics. 2021; 13 (9): 1461.

23. Abboud A.R., Ali A.M., Youssef T. Preparation and characterization of insulin-loaded injectable hydrogels as potential adjunctive periodontal treatment. Dental and Medical Problems. 2020; 57 (4): 377-84.

24. Chanaj-Kaczmarek, Justyna, et al. Development and Evaluation of Thermosensitive Hydrogels with Binary Mixture of Scutellariae baicalensis radix Extract and Chitosan for Periodontal Diseases Treatment. International Journal of Molecular Sciences. 2021; 22 (21): 11319.

25. Ammar M.M., Waly G.H., Saniour S.H., Moussa T.A. Growth factor release and enhanced encapsulated periodontal stem cells viability by freeze-dried platelet concentrate loaded thermo-sensitive hydrogel for periodontal regeneration. The Saudi Dental Journal. 2018; 30 (4): 355-64.

26. Wu S., Zhou Y., et al. Evaluation of Chitosan Hydrogel for Sustained Delivery of VEGF for Odontogenic Differentiation of Dental Pulp Stem Cells. 2019; 2019: 1515040.

27. Renard E., Amiaud J., Delbos L., Charrier C., Montembault A., Ducret M., et al. Dental pulp inflammatory/immune response to a chitosan-enriched fibrin hydrogel in the pulpotomised rat incisor. European Cells & Materials. 2020; 40: 74-87.

28. Moreira M.S., Sarra G., et al. Physical and Biological Properties of a Chitosan Hydrogel Scaffold Associated to Photobiomodulation Therapy for Dental Pulp Regeneration: An In Vitro and In Vivo Study. BioMed Research International. 2021; 2021: 6684667.

29. Divband B., Pouya B., et al. Towards Induction of Angiogenesis in Dental Pulp Stem Cells Using Chitosan-Based Hydrogels Releasing Basic Fibroblast Growth Factor. BioMed Research International. 2022; 2022: 5401461.

30. Erten Taysi A., Cevher E., et al. The efficacy of sustained-release chitosan microspheres containing recombinant human parathyroid hormone on MRONJ. Brazilian Oral Research 2019; 33: e086.

31. Hosny K.M., Sindi A.M., Alkhalidi H.M., Kurakula M., Alruwaili N.K., Alhakamy N.A., et al. Oral gel loaded with penciclovir-lavender oil nanoemulsion to enhance bioavailability and alleviate pain associated with herpes labialis. Drug Delivery. 2021; 28 (1): 1043-54.