Inhibition of Periodontitis Induction Using a Stimuli-Responsive Hydrogel Carrying Naringin

• Autores: Po-Chun Chang, Yi Chi Chao, Meng Hsuan Hsiao, Hao Syun Chou, Yi-Han Jheng, Xin Hong Yu, Ning Lee, Connie Yang, Dean Mo Liu
• Localización: Journal of periodontology, ISSN 0022-3492, Vol. 88, Nº. 2, 2017, págs. 190-196
• Idioma: inglés
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• Resumen

  • Background: Developing a drug carrier with favorable handling characteristics that can respond to environmental changes after inflammation, such as pH changes, may be beneficial for treating periodontitis. This study aims to investigate the preclinical feasibility of using naringin, a naturally derived polymethoxylated flavonoid compound with anti-inflammatory properties, to inhibit periodontitis induction via a thermogelling and pH-responsive injectable hydrogel.

    Methods: The hydrogel was made of amphipathic carboxymethyl-hexanoyl chitosan (CHC), β-glycerol phosphate (β-GP), and glycerol. Thermogelling and pH-responsive characteristics of the hydrogel, as well as cell viability after treatment with the hydrogel containing naringin, were evaluated in vitro. Hydrogel was subgingivally delivered when experimental periodontitis was induced in vivo, and therapeutic effect was evaluated with microcomputed tomography imaging, histology, and expression of inflammation-associated genes, including toll-like receptor (TLR)2, the receptor for advanced glycation end products (RAGE), myeloid differentiation primary response gene-88, and tumor necrosis factor (TNF)-α.

    Results: The hydrogel was consistently fluidic at 4°C but rapidly gelled at 37°C. Release of naringin was faster at pH 5.5 to 6.5, and viability was significantly promoted by treatment with 0.85% naringin. Naringin-carrying CHC-β-GP-glycerol hydrogel sites showed significantly reduced periodontal bone loss (P <0.05) and inflammatory infiltration (P <0.01) as well as significantly downregulated TLR2 (P <0.05), RAGE (P <0.01), and TNF-α (P <0.05) relative to the sites with experimental periodontitis alone.

    Conclusion: Naringin-carrying CHC-β-GP-glycerol colloidal hydrogel can be used to inhibit induction of experimental periodontitis with favorable handling and inflammation-responsive characteristics.

    Periodontitis is caused by bacteria-induced inflammation and is characterized by damage of the periodontium, including alveolar bone, periodontal ligament, and cementum.1,2 Progressive loss of the periodontium causes loosening and subsequent loss of teeth, and the rationale for periodontal treatment is to reduce inflammation through mechanical debridement to relieve complications and restore chewing function.3 Modification of the inflammatory response via local delivery of chemicals (i.e., drugs) into the gingival sulcus has emerged as a potential treatment modality for periodontitis.4 Local delivery of chemicals provides several advantages; in addition to preventing activation of the systemic immune response, the chemical could be targeted directly to the tooth and periodontal interface (periodontal pocket) and, thus, the chemical dose could be minimized.5 Vehicles to subgingivally deliver antibiotics or chlorhexidine have been clinically introduced to reduce infection and control the inflammatory status of periodontitis.6 These vehicles are characterized by good biocompatibility, biodegradability, a sustained local therapeutic effect, and easy handling.7 Recently, there has been growing interest in developing a drug carrier that can respond to specific stimuli from a disease.8 Because inflammation may lead to a relatively acidic environment,9 and a minor acidic environment (pH 5.0 to 7.0) was shown to be favorable for the growth of several periodontal pathogens (e.g., Prevotella intermedia and Fusobacterium nucleatum), a pH-triggered drug delivery system could be a solution for treating periodontitis.10 Chitosan has been considered a candidate due to its greater solubility in lower pH conditions.11 By adding glycerol-phosphate salts and a partial substitution with carboxymethyl-hexanoyl groups, a chitosan-based thermogelling carrier with a favorable drug-loading capability was developed.11 The carboxymethyl-hexanoyl chitosan (CHC) possesses an amphiphilic nature that makes it capable of encapsulating either hydrophilic or hydrophobic drugs as well as a combination of drugs. Under optimal gelling conditions, the CHC solution can aggregate into a solid-like colloidal hydrogel after adding glycerol-phosphate salts. This CHC hydrogel has displayed a number of interesting physical and biologic characteristics, including shear-reversible assembly, biodegradability, sustain-to-burst release control, and excellent biocompatibility,12 that make the injectable hydrogel a great potential vehicle for delivering periodontal medicine.

    On the other hand, although antibiotics have been clinically applied in treating the mixed infection of periodontitis, efficacy of antibiotics is usually limited, and bacterial resistance against antibiotics might develop.13-15 Naringin, a polymethoxylated flavonoid and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae),16 has been considered a naturally derived alternative for treating periodontitis based on its inhibitory effects on Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis17 as well as on inflammation induced by lipopolysaccharides (LPS).18 It has also been suggested that naringin has antioxidative, antimutagenic, and anticarcinogenic effects.19 However, the therapeutic value of naringin in treating periodontitis in vivo has yet to be evaluated.

    This study aimed to validate the preclinical feasibility of the chitosan-based thermosensitive and pH-responsive hydrogel with naringin, a potential medicine with antibacterial and anti-inflammatory effects, to inhibit induction of experimental periodontitis.