Ning Haoran, Wu Xiaowei, Wu Qing, Yu Wanlu, Wang Huaiji, Zheng Shang, Chen Yunong, Li Yongyong, Su Jiansheng
Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China.
Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 10081, China.
ACS Biomater Sci Eng. 2019 May 13;5(5):2430-2443. doi: 10.1021/acsbiomaterials.8b01468. Epub 2019 Apr 22.
Severe adverse reactions of bisphosphonates and anti-resorptive or anti-angiogenic medications, termed medication-related osteonecrosis of the jaw (MRONJ), have been reported. MRONJ are difficult to completely cure and could cause great pain to patients. Recent studies have shown that mesenchymal stem cell (MSC) therapies are effective for treating MRONJ, but the method of intravenous injection is unstable and increases the risk of producing tumors. In the present study, low-acyl gellan gum (LAGG) hydrogels were modified with hemicellulose polysaccharide microfibers (PMs) to improve the performance of supporting three-dimensional (3D) cell growth. LAGG-PM composite hydrogels were found to be nontoxic to rat adipose-derived stem cells (rADSCs) . The hydrogels also promoted the secretion of angiogenic factors, induced osteoclastogenesis by conditioned medium, and supported osteogenic marker expression after the addition of human bone morphogenetic protein-2 (BMP-2). Due to its injectability, the LAGG-PM composite hydrogel incorporated with rADSCs and BMP-2 could be applied into the MRONJ lesion site, which promoted mucosal recovery, bone tissue reconstruction, and osteoclastogenesis. This study confirms the potential applications of LAGG-PM composite hydrogels as 3D cell culture platforms and delivery vehicles for the treatment of MRONJ in a rat model.
双膦酸盐以及抗吸收或抗血管生成药物的严重不良反应，即药物相关性颌骨坏死（MRONJ），已有报道。MRONJ难以完全治愈，会给患者带来巨大痛苦。最近的研究表明，间充质干细胞（MSC）疗法对治疗MRONJ有效，但静脉注射方法不稳定且会增加产生肿瘤的风险。在本研究中，用半纤维素多糖微纤维（PMs）对低酰基结冷胶（LAGG）水凝胶进行改性，以改善其支持三维（3D）细胞生长的性能。发现LAGG-PM复合水凝胶对大鼠脂肪来源干细胞（rADSCs）无毒。该水凝胶还能促进血管生成因子的分泌，通过条件培养基诱导破骨细胞生成，并在添加人骨形态发生蛋白-2（BMP-2）后支持成骨标志物的表达。由于其可注射性，结合了rADSCs和BMP-2的LAGG-PM复合水凝胶可应用于MRONJ病变部位，促进黏膜恢复、骨组织重建和破骨细胞生成。本研究证实了LAGG-PM复合水凝胶作为3D细胞培养平台和治疗大鼠模型中MRONJ的递送载体的潜在应用。
