Mucus-Inspired Drug-Loaded Bottlebrush Polymer Hydrogel With Easy-Removable and Shear-Thinning Characteristics Enables Effective Treatment of Persistent Root Canal Infection

Abstract

Existing hydrogels pose challenges for the applications in transitional medication within narrow cavities due to the inherent conflict between fluidity and shape retention. Herein, inspired by mucus, a bottlebrush polymer hydrogel (denoted as PH-PG-T hydrogel) with excellent injectability, stable antibacterial property, and easy removability is developed by grafting poly(ethylene glycol) methyl ether methacrylate side-chains from polyhydroxyethyl methacrylate backbones and incorporating triple antibiotics. As a transitional disinfectant in tooth root canal treatment, PH-PG-T hydrogel fulfills requirements for an ideal disinfectant thorough treatment process. The polymer side-chains of PH-PG-T hydrogel disentangle during injection to facilitate canal filling and rapidly re-entangle after injection to enable in situ gelation and sustained antibiotics release. After medication, PH-PG-T hydrogel quickly dissolves in water during irrigation, facilitating its complete removal from the root canal. These findings highlight a promising avenue for the novel application of bottlebrush polymers as a high-performance disinfectant to control persistent root canal infections.

Keywords

bottlebrush polymer hydrogel / injectable / periapical periodontitis / root canal disinfectants / shear-thinning

References

[1] Y. S. Zhang and A. Khademhosseini, “Advances in Engineering Hydrogels,” Science 356, no. 6337 (2017): eaaf3627.

[2] J. J. Green and J. H. Elisseeff, “Mimicking Biological Functionality With Polymers for Biomedical Applications,” Nature 540 (2016): 386–394.

[3] P. Bertsch, M. Diba, D. J. Mooney, and S. C. G. Leeuwenburgh, “Self-Healing Injectable Hydrogels for Tissue Regeneration,” Chemical Reviews 123, no. 2 (2023): 834–873.

[4] C. S. Tibúrcio-Machado, C. Michelon, F. B. Zanatta, M. S. Gomes, J. A. Marin, and C. A. Bier, “The Global Prevalence of Apical Periodontitis: A Systematic Review and Meta-Analysis,” International Endodontic Journal 54, no. 5 (2021): 712–735.

[5] X. Zou, X. Zheng, Y. Liang, et al., “Expert Consensus on Irrigation and Intracanal Medication in Root Canal Therapy,” International Journal of Oral Science 16, no. 23 (2024): 23.

[6] L. H. Berman and K. M. Hargreaves, Cohen's Pathways of the Pulp (Elsevier, 2021). 12th ed., 281–284.

[7] B. Marroquin, M. El-Sayed, and B. Willershausenzonnchen, “Morphology of the Physiological Foramen: I. Maxillary and Mandibular Molars,” Journal of Endodontics 30, no. 5 (2004): 321–328.

[8] T. Xu, F. R. Tay, J. L. Gutmann, et al., “Micro Computed Tomography Assessment of Apical Accessory Canal Morphologies,” Journal of Endodontics 42, no. 5 (2016): 798–802.

[9] M. A. Versiani, J. D. Pécora, and M. D. Sousa-Neto, “Microcomputed Tomography Analysis of the Root Canal Morphology of Single-Rooted Mandibular Canines,” International Endodontic Journal 46, no. 9 (2013): 800–807.

[10] I. A. Mjör and I. Nordahl, “The Density and Branching of Dentinal Tubules in Human Teeth,” Archives of Oral Biology 41, no. 5 (1996): 401–412.

[11] K. V. Teja, K. Janani, K. C. Srivastava, et al., “Comparative Evaluation of Antimicrobial Efficacy of Different Combinations of Calcium Hydroxide Against Enterococcus faecalis,” BMC Oral Health 23, no. 1 (2023): 849.

[12] T. Rödig, M. Hirschleb, A. Zapf, and M. Hülsmann, “Comparison of Ultrasonic Irrigation and RinsEndo for the Removal of Calcium Hydroxide and Ledermix Paste From Root Canals,” International Endodontic Journal 44, no. 12 (2011): 1155–1161.

[13] C. Stuart, S. Schwartz, T. Beeson, and C. Owatz, “Enterococcus faecalis: Its Role in Root Canal Treatment Failure and Current Concepts in Retreatment,” Journal of Endodontics 32, no. 2 (2006): 93–98.

[14] K. Karamifar, A. Tondari, and M. A. Saghiri, “Endodontic Periapical Lesion: An Overview on the Etiology, Diagnosis and Current Treatment Modalities,” European Endodontic Journal 5, no. 2 (2020): 54–67.

[15] M. E. F. Arruda, M. A. S. Neves, A. Diogenes, et al., “Infection Control in Teeth With Apical Periodontitis Using a Triple Antibiotic Solution or Calcium Hydroxide With Chlorhexidine: A Randomized Clinical Trial,” Journal of Endodontics 44, no. 10 (2018): 1474–1479.

[16] M. Dioguardi, C. Quarta, M. Alovisi, et al., “Microbial Association With Genus Actinomyces in Primary and Secondary Endodontic Lesions, Review,” Antibiotics (USSR) 9, no. 8 (2020): 433.

[17] D. K. Lee, S. V. Kim, A. N. Limansubroto, et al., “Nanodiamond–Gutta Percha Composite Biomaterials for Root Canal Therapy,” ACS Nano 9, no. 11 (2015): 11490–11501.

[18] Y. Cheng, Y. Huangfu, T. Zhao, et al., “Thermosensitive Hydrogel With Programmed Dual-Octenidine Release Combating Biofilm for the Treatment of Apical Periodontitis,” Regenerative Biomaterials 11 (2024): rbae031.

[19] T. Li, Y. Luo, S. Wu, et al., “Super-Rapid In Situ Formation of a Silver Ion-Induced Supramolecular Hydrogel With Efficient Antibacterial Activity for Root Canal Disinfection,” ACS Applied Materials & Interfaces 15, no. 25 (2023): 29854–29865.

[20] R. Dal-Fabbro, Y. C. Huang, P. T. A. Toledo, et al., “Injectable Methacrylated Gelatin Hydrogel for Safe Sodium Hypochlorite Delivery in Endodontics,” Gels 9, no. 11 (2023): 897.

[21] J. Zhu, M. Zhang, R. Qiu, et al., “Hagfish-Inspired Hydrogel for Root Caries: A Multifunctional Approach Including Immediate Protection, Antimicrobial Phototherapy, and Remineralization,” Acta Biomaterialia 188 (2024): 117–137.

[22] R. Bej and R. Haag, “Mucus-Inspired Dynamic Hydrogels: Synthesis and Future Perspectives,” Journal of the American Chemical Society 144, no. 44 (2022): 20137–20152.

[23] R. Bansil and B. S. Turner, “The Biology of Mucus: Composition, Synthesis and Organization,” Advanced Drug Delivery Reviews 124 (2018): 3–15.

[24] J. M. Newby, I. Seim, M. Lysy, et al., “Technological Strategies to Estimate and Control Diffusive Passage Times Through the Mucus Barrier in Mucosal Drug Delivery,” Advanced Drug Delivery Reviews 124 (2018): 64–81.

[25] D. A. Subramanian, R. Langer, and G. Traverso, “Mucus Interaction to Improve Gastrointestinal Retention and Pharmacokinetics of Orally Administered Nano-Drug Delivery Systems,” Journal of Nanobiotechnology 20 (2022): 362.

[26] H. M. A. Ahmed, M. A. Versiani, G. De-Deus, and P. M. H. Dummer, “A New System for Classifying Root and Root Canal Morphology,” International Endodontic Journal 50, no. 8 (2017): 761–770.

[27] S. Dai, G. Xiao, N. Dong, F. Liu, S. He, and Q. Guo, “Bactericidal Effect of a Diode Laser on Enterococcus faecalis in Human Primary Teeth—An In Vitro Study,” BMC Oral health 18, no. 1 (2018): 154.

[28] S. Jeong, D. A. Greenfield, M. Hermsmeier, et al., “Time-Resolved Fluorescence Microscopy With Phasor Analysis for Visualizing Multicomponent Topical Drug Distribution Within Human Skin,” Scientific Reports 10 (2020): 5360.

[29] H. Luo, M. Szymusiak, E. A. Garcia, et al., “Solute-Triggered Morphological Transitions of an Amphiphilic Heterografted Brush Copolymer as a Single-Molecule Drug Carrier,” Macromolecules 50, no. 5 (2017): 2201–2206.

[30] K. E. Barr, M. L. Ohnsorg, L. Liberman, et al., “Drug–Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810,” Bioconjugate Chemistry 35, no. 4 (2024): 499–516.

[31] J. F. Siqueira, I. N. Rôças, D. Ricucci, and M. Hülsmann, “Causes and Management of Post-Treatment Apical Periodontitis,” British Dental Journal 216, no. 6 (2014): 305–312.

[32] M. Evans, J. K. Davies, G. Sundqvist, and D. Figdor, “Mechanisms Involved in the Resistance of Enterococcus faecalis to Calcium Hydroxide,” International Endodontic Journal 35, no. 3 (2002): 221–228.

[33] M. Papageorgiou, I. Kitsou, P. Gkomoza, A. A. Alivisatou, J. Papaparaskevas, and A. Tsetsekou, “Bioinspired Synthesis of Multifunctional, Highly Stable Polymeric Templated Silver-Silica Colloids as Catalytic and Antibacterial Coatings for Paper,” Colloids and Surfaces B: Biointerfaces 240 (2024): 113997.

[34] I. Sangita, S. Vishwanath, K. Sadasiva, A. Ramachandran, Y. Thanikachalam, and V. Ramya, “Influence of Simulated Wound Exudate on the Antimicrobial Efficacy of Various Intracanal Medicaments Against Enterococcus faecalis: An In Vitro Study,” Cureus 15, no. 5 (2023): e38677.

[35] J. C. M. Oliveira, F. R. F. Alves, M. Uzeda, I. N. Rôças, and J. F. Siqueira,, “Influence of Serum and Necrotic Soft Tissue on the Antimicrobial Effects of Intracanal Medicaments,” Brazilian Dental Journal 21, no. 4 (2010): 295–300.

[36] P. Kaiser, J. Wächter, and M. Windbergs, “Therapy of Infected Wounds: Overcoming Clinical Challenges by Advanced Drug Delivery Systems,” Drug Delivery and Translational Research 11, no. 4 (2021): 1545–1567.

[37] Q. Li, Q. Zhang, X. Zou, and L. Yue, “Evaluation of Four Final Irrigation Protocols for Cleaning Root Canal Walls,” International Journal of Oral Science 12 (2020): 29.

[38] L. Chen, M. Peng, H. Li, et al., “Metal-Phenolic Network With Pd Nanoparticle Nodes Synergizes Oxidase-Like and Photothermal Properties to Eradicate Oral Polymicrobial Biofilm-Associated Infections,” Advanced Materials 36, no. 7 (2024): e2306376.

[39] X. Duan, Q. Zhang, Y. Jiang, et al., “Semiconducting Polymer Nanoparticles With Intramolecular Motion-Induced Photothermy for Tumor Phototheranostics and Tooth Root Canal Therapy,” Advanced Materials 34, no. 17 (2022): e2200179.

[40] T. Shao, R. Guan, C. Zhang, and B. Hou, “Influence of Operator's Experience on Complications of Root Canal Treatment Using Contemporary Techniques: A Retrospective Study,” BMC Oral health 24, no. 1 (2024): 96.

[41] I. D. Capar, E. Ozcan, H. Arslan, H. Ertas, and H. A. Aydinbelge, “Effect of Different Final Irrigation Methods on the Removal of Calcium Hydroxide From an Artificial Standardized Groove in the Apical Third of Root Canals,” Journal of Endodontics 40, no. 3 (2014): 451–454.

[42] L. Robberecht, J. Delattre, and M. Meire, “Isthmus Morphology Influences Debridement Efficacy of Activated Irrigation: A Laboratory Study Involving Biofilm Mimicking Hydrogel Removal and High-Speed Imaging,” International Endodontic Journal 56, no. 1 (2023): 118–127.

[43] R. Wigler, R. Dvir, A. Weisman, S. Matalon, and A. Kfir, “Efficacy of XP-Endo Finisher Files in the Removal of Calcium Hydroxide Paste From Artificial Standardized Grooves in the Apical Third of Oval Root Canals,” International Endodontic Journal 50, no. 7 (2017): 700–705.

[44] S. Nandini, N. Velmurugan, and D. Kandaswamy, “Removal Efficiency of Calcium Hydroxide Intracanal Medicament With Two Calcium Chelators: Volumetric Analysis Using Spiral CT, an In Vitro Study,” Journal of Endodontics 32, no. 11 (2006): 1097–1101.

RIGHTS & PERMISSIONS

2025 The Authors. SmartMat published by Tianjin University and John Wiley & Sons Australia, Ltd.