Adhesive and injectable hydrogel microspheres for NRF2-mediated periodontal bone regeneration

Abstract

Regenerating periodontal bone defect surrounding periodontal tissue is crucial for orthodontic or dental implant treatment. The declined osteogenic ability of periodontal ligament stem cells (PDLSCs) induced by inflammation stimulus contributes to reduced capacity to regenerate periodontal bone, which brings about a huge challenge for treating periodontitis. Here, inspired by the adhesive property of mussels, we have created adhesive and mineralized hydrogel microspheres loaded with traditional compound cordycepin (MMS-CY). MMS-CY could adhere to the surface of alveolar bone, then promote the migration capacity of PDLSCs and thus recruit them to inflammatory periodontal tissues. Furthermore, MMS-CY rescued the impaired osteogenesis and ligament-forming capacity of PDLSCs, which were suppressed by the inflammation stimulus. Moreover, MMS-CY also displayed the excellent inhibitory effect on the osteoclastic activity. Mechanistically, MMS-CY inhibited the premature senescence induced by the inflammation stimulus through the nuclear factor erythroid 2-related factor (NRF2) pathway and reducing the DNA injury. Utilizing in vivo rat periodontitis model, MMS-CY was demonstrated to enhance the periodontal bone regeneration by improving osteogenesis and inhibiting the osteoclastic activity. Altogether, our study indicated that the multi-pronged approach is promising to promote the periodontal bone regeneration in periodontitis condition by reducing the inflammation-induced stem cell senescence and maintaining bone homeostasis.

References

[1] Slots J. Periodontitis: facts, fallacies and the future Periodontol 2000, 2017, 75: 7-23.

[2] Deas DE, Moritz AJ, Sagun RS Jr., Gruwell SF, Powell CA. Scaling and root planing vs. conservative surgery in the treatment of chronic periodontitis Periodontol 2000, 2016, 71: 128-139.

[3] Graetz C, Schorr S, Christofzik D, Dörfer CE, Sälzer S. How to train periodontal endoscopy? Results of a pilot study removing simulated hard deposits in vitro Clin. Oral. Investig., 2020, 24: 607-617.

[4] Xu XY, et al.. Concise review: periodontal tissue regeneration using stem cells: strategies and translational considerations Stem Cells Transl. Med., 2019, 8: 392-403.

[5] Liu X, et al.. Piezoelectric hydrogel for treatment of periodontitis through bioenergetic activation Bioact. Mater., 2024, 35: 346-361

[6] Julier Z, et al.. Enhancing the regenerative effectiveness of growth factors by local inhibition of interleukin-1 receptor signaling Sci. Adv., 2020, 6. eaba7602

[7] Dodson M, Anandhan A, Zhang DD, Madhavan L. An NRF2 perspective on stem cells and ageing Front Aging, 2021, 2: 690686.

[8] Zhang CY, et al.. EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis Redox Biol., 2023, 63. 102765

[9] Pyun, B. J., et al. Caesalpinia sappan Linn. Ameliorates Allergic Nasal Inflammation by Upregulating the Keap1/Nrf2/HO-1 pathway in an allergic rhinitis mouse model and nasal epithelial cells. Antioxidants (Basel) 11, 2256 (2022).

[10] Lee, D., et al. The inhibitory effect of cordycepin on the proliferation of MCF-7 breast cancer cells, and its mechanism: an investigation using network pharmacology-based analysis. Biomolecules 9, 407 (2019).

[11] Wang Z, et al.. Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents Nat. Commun., 2019, 10. 2538

[12] Dou C, et al.. Cordycepin prevents bone loss through inhibiting osteoclastogenesis by scavenging ROS generation Nutrients, 2016, 8: 231.

[13] Marslin G, Khandelwal V, Franklin G. Cordycepin Nanoencapsulated in Poly(Lactic-Co-Glycolic Acid) exhibits better cytotoxicity and lower hemotoxicity than free drug Nanotechnol. Sci. Appl, 2020, 13: 37-45.

[14] Yu Y, et al.. Recent advances in thermo-sensitive hydrogels for drug delivery J. Mater. Chem. B, 2021, 9: 2979-2992.

[15] Hooshiar MH, et al.. Recent advances in nanomaterial-based biosensor for periodontitis detection J. Biol. Eng., 2024, 18. 28

[16] Santos, M. S., Dos Santos, A. B. & Carvalho, M. S. New insights in hydrogels for periodontal regeneration. J. Funct. Biomater. 14, 545 (2023).

[17] Zhang Q, et al.. Mussel-inspired polydopamine-modified biochar microsphere for reinforcing polylactic acid composite films: Emphasizing the achievement of excellent thermal and mechanical properties Int. J. Biol. Macromol., 2024, 260. 129567

[18] Cheng W, et al.. Versatile polydopamine platforms: synthesis and promising applications for surface modification and advanced nanomedicine ACS Nano, 2019, 13: 8537-8565.

[19] Wei P, Yuan Z, Cai Q, Mao J, Yang X. Bioresorbable microspheres with surface-loaded nanosilver and apatite as dual-functional injectable cell carriers for bone regeneration Macromol. Rapid Commun., 2018, 39. e1800062

[20] Zhang D, et al.. Lepr-expressing PDLSCs contribute to periodontal homeostasis and respond to mechanical force by Piezo1 Adv. Sci. (Weinh.), 2023, 10 e2303291

[21] Wu W, et al.. Bomidin attenuates inflammation of periodontal ligament stem cells and periodontitis in mice via inhibiting ferroptosis Int. Immunopharmacol., 2024, 127. 111423

[22] Kinoshita, M., et al. Mice Lacking PLAP-1/Asporin show alteration of periodontal ligament structures and acceleration of bone loss in periodontitis. Int. J. Mol. Sci. 24, 15989 (2023).

[23] Zou R, et al.. Combining enamel matrix proteins with mechanical stimuli potentiates human periodontal ligament fibroblasts proliferation and periodontium remodeling Histol. Histopathol., 2018, 33: 825-833

[24] Theilig C, Bernd A, Leyhausen G, Kaufmann R, Geurtsen W. Effects of mechanical force on primary human fibroblasts derived from the gingiva and the periodontal ligament J. Dent. Res., 2001, 80: 1777-1780.

[25] Zhang X, Schuppan D, Becker J, Reichart P, Gelderblom HR. Distribution of undulin, tenascin, and fibronectin in the human periodontal ligament and cementum: comparative immunoelectron microscopy with ultra-thin cryosections J. Histochem Cytochem, 1993, 41: 245-251.

[26] Du J, Li M. Functions of periostin in dental tissues and its role in periodontal tissue regeneration Adv. Exp. Med. Biol., 2019, 1132: 63-72.

[27] Ma Y, et al.. Resveratrol modulates the inflammatory response in hPDLSCs via the NRF2/HO-1 and NF-κB pathways and promotes osteogenic differentiation J. Periodontal Res., 2024, 59: 162-173.

[28] Aquino-Martinez R. The emerging role of accelerated cellular senescence in periodontitis J. Dent. Res, 2023, 102: 854-862.

[29] Arvanitaki ES, Stratigi K, Garinis GA. DNA damage, inflammation and aging: Insights from mice Front Aging, 2022, 3: 973781.

[30] Feng B, et al.. Fidelity-oriented fluorescence imaging probes for beta-galactosidase: From accurate diagnosis to precise treatment Biotechnol. Adv., 2023, 68. 108244

[31] Li, C., et al. Autoinducer-2 produced by oral microbial flora and alveolar bone loss in periodontitis. J. Periodontal. Res. 59, 576–588 (2024).

[32] Sadek, K. M., et al. Molecular basis beyond interrelated bone resorption/regeneration in periodontal diseases: A concise review. Int. J. Mol. Sci. 24, 4599 (2023).

[33] Staples RJ, Ivanovski S, Vaquette C. Fibre guiding scaffolds for periodontal tissue engineering J. Periodontal. Res., 2020, 55: 331-341.

[34] Liu C, Chen Y, Bai H, Niu Y, Wu Y. Characterization and application of in situ curcumin/ZNP hydrogels for periodontitis treatment BMC Oral. Health, 2024, 24. 395

[35] Li X, Wu X. The microspheres/hydrogels scaffolds based on the proteins, nucleic acids, or polysaccharides composite as carriers for tissue repair: A review Int J. Biol. Macromol., 2023, 253: 126611.

[36] Zhou L, et al.. Immune-defensive microspheres promote regeneration of the nucleus pulposus by targeted entrapment of the inflammatory cascade during intervertebral disc degeneration Bioact. Mater., 2024, 37: 132-152

[37] Cai Y, et al.. Mussel-inspired controllable drug release hydrogel for transdermal drug delivery: Hydrogen bond and ion-dipole interactions J. Control Release, 2024, 365: 161-175.

[38] Guo Q, Chen J, Wang J, Zeng H, Yu J. Recent progress in synthesis and application of mussel-inspired adhesives Nanoscale, 2020, 12: 1307-1324.

[39] Abedi M, Ghasemi Y, Nemati MM. Nanotechnology in toothpaste: Fundamentals, trends, and safety Heliyon, 2024, 10: e24949.

[40] Yang SY, et al.. Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway J. Nanobiotechnology, 2024, 22. 94

[41] Dyachkova, U., Vigovskiy, M., Basalova, N., Efimenko, A. & Grigorieva, O. M2-macrophage-induced chronic inflammation promotes reversible mesenchymal stromal cell senescence and reduces their anti-fibrotic properties. Int. J. Mol. Sci. 24, 17089 (2023).

[42] Wang Y, et al.. Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells Bone Res., 2023, 11: 54.

[43] Lee SJ, et al.. Transglutaminase 2 prevents premature senescence and promotes osteoblastic differentiation of mesenchymal stem cells through NRF2 Activation Stem Cells Int., 2023, 2023. 8815888

[44] He H, et al.. Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function Nat. Aging, 2024, 4: 510-526.

[45] Jin S, et al.. Young exosome bio-nanoparticles restore aging-impaired tendon stem/progenitor cell function and reparative capacity Adv. Mater., 2023, 35. e2211602

RIGHTS & PERMISSIONS

The Author(s)