Application Of Nanocomposite Hydrogels With Multiple Response Properties In The Treatment Of Diabetic Periodontitis

Injectable hydrogel drug delivery systems offer advantages in terms of prolonged drug release cycles,improved drug bioavailability,and the ability to modify the hydrogel material to obtain smart stimulus-responsive hydrogels.Stimulus-responsive hydrogels loaded with multiple drugs have shown advantages in terms of tunable and sustained drug release.In this paper,a combined antibiotic/endoplasmic reticulum stress inhibitor topically delivered loaded in a smart responsive hydrogel was developed for the treatment of diabetic periodontitis and investigated for its application.The main studies were conducted on the following aspects.（1）Construction of a topical drug carrier with glucose/reactive oxygen/acid multi-responsive organic/inorganic nanocomposite hydrogel composed of n Ca CO₃ aqueous phase dispersion,polyvinyl alcohol（PVA）and phenylboronic acid grafted hyaluronic acid（HA-APBA）and its application to the combination of antibiotic（minocycline hydrochloride）and endoplasmic reticulum stress inhibitor（GSK2606414）for the treatment of diabetic severe periodontitis.Small size,uniform particle size and good dispersion of n Ca CO₃ were prepared by combining supergravity and polymer-induced liquid precursor techniques.n Ca CO₃ was successfully grafted on HA-APBA and its ratio to PVA was regulated to produce a smart stimulus-responsive hydrogel,and drug-laden inorganic nanoparticles were loaded into the hydrogel.The in vitro drug release behavior of the drug-loaded hydrogels was investigated under different environments.The drug-loaded hydrogels showed higher drug release rate under high glucose concentration,acidic environment and high hydrogen peroxide concentration,which demonstrated the multi-response property of the composite hydrogels.（2）In vitro cytological studies were performed on the hydrogel containing MINO alone（NCMH）.The excellent antibacterial properties of NCMH hydrogels and their ability to promote osteogenic differentiation and mineralization of periodontal stem cells were demonstrated by biological assays such as cytotoxicity,bacteriostatic properties and osteogenic capacity.The functional mechanism of GSK2606414 hydrogel（NCGH）on LPS-mediated endoplasmic reticulum stress activation affecting PDLSCs was investigated separately.The effects of hydrogel formulation on the growth,proliferation and cell cycle of PDLSCs were investigated by cell proliferation assay,q RT-PCR method to detect the mechanism of UPR signaling pathway interfering with endoplasmic reticulum stress,q RT-PCR method to detect the mechanism of PERK signaling pathway interfering with endoplasmic reticulum stress,apoptosis and reactive oxygen species assay,which demonstrated that GSK2606414hydrogel controlled release agent could effectively restore LPS-mediated endoplasmic reticulum stress response in PDLSCs,thus effectively restoring the osteogenic capacity of the cells.To explore the optimal drug ratio of minocycline hydrochloride/GSK2606414 combined hydrogel controlled release agent,the osteogenic differentiation ability of PDLSCs due to LPS-induced endoplasmic reticulum stress was effectively reversed by the combined hydrogel system as demonstrated by the osteogenic ability assay.（3）In vivo animal studies on the efficacy of minocycline MINO/GSK2606414 combined with hydrogel controlled release agent.A SD rat model of diabetic periodontitis was constructed,the gingival sulcus of SD rats was administered by local injection,the extent of alveolar bone damage was evaluated by Micro-CT,and the alveolar teeth and surrounding gingiva were taken for H&E staining,Masson staining,and immunohistochemical staining analysis.Compared with the injection of single drug hydrogel controlled release,the combined administration of hydrogel controlled release system showed superior regeneration of alveolar bone defects and periodontal tissue repair and reconstruction,which brings more efficient treatment and good application prospects for patients with diabetic severe periodontitis.