Engineering multifunctional hydrogel systems capable of amplifying the regenerative capacity of endogenous progenitor cells via localized presentation of therapeutics under tissue inflammation is central to the translation of effective strategies for hard tissue regeneration. Here, we loaded dexamethasone (DEX), a pleotropic drug with anti-inflammatory and mineralizing abilities, into aluminosilicate clay nanotubes (halloysite clay nanotubes (HNTs)) to engineer an injectable multifunctional drug delivery system based on photo-cross-linkable gelatin methacryloyl (GelMA) hydrogel. In detail, a series of hydrogels based on GelMA formulations containing distinct amounts of DEX-loaded nanotubes was analyzed for physicochemical and mechanical properties and kinetics of DEX release as well as compatibility with mesenchymal stem cells from human exfoliated deciduous teeth (SHEDs). The anti-inflammatory response and mineralization potential of the engineered hydrogels were determined in vitro and in vivo. DEX conjugation with HNTs was confirmed by FTIR analysis. The incorporation of DEX-loaded nanotubes enhanced the mechanical strength of GelMA with no effect on its degradation and swelling ratio. Scanning electron microscopy (SEM) images demonstrated the porous architecture of GelMA, which was not significantly altered by DEX-loaded nanotubes’ (HNTs/DEX) incorporation. All GelMA formulations showed cytocompatibility with SHEDs (p < 0.05) regardless of the presence of HNTs or HNTs/DEX. However, the highest osteogenic cell differentiation was noticed with the addition of HNT/DEX 10% in GelMA formulations (p < 0.01). The controlled release of DEX over 7 days restored the expression of alkaline phosphatase and mineralization (p < 0.0001) in lipopolysaccharide (LPS)-stimulated SHEDs in vitro. Importantly, in vivo data revealed that DEX-loaded nanotube-modified GelMA (5.0% HNT/DEX 10%) led to enhanced bone formation after 6 weeks (p < 0.0001) compared to DEX-free formulations with a minimum localized inflammatory response after 7 days. Altogether, our findings show that the engineered DEX-loaded nanotube-modified hydrogel may possess great potential to trigger in situ mineralized tissue regeneration under inflammatory conditions.

中文翻译：

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炎症微环境下用于硬组织再生的可注射多功能给药系统

工程化多功能水凝胶系统能够通过在组织炎症下局部呈现治疗剂来放大内源性祖细胞的再生能力，这对于转化硬组织再生的有效策略至关重要。在这里，我们将地塞米松 (DEX)，一种具有抗炎和矿化能力的多效药物装入硅铝酸盐粘土纳米管（埃洛石粘土纳米管 (HNTs)）中，以设计一种基于可光交联明胶甲基丙烯酰基的可注射多功能药物递送系统。 GelMA) 水凝胶。详细地，分析了一系列基于 GelMA 配方的水凝胶，这些水凝胶含有不同数量的 DEX 负载纳米管，其物理化学和机械性能以及 DEX 释放的动力学以及与来自人类脱落乳牙 (SHED) 的间充质干细胞的相容性。确定了工程水凝胶的抗炎反应和矿化潜力体外和体内。FTIR 分析证实了 DEX 与 HNT 的结合。负载 DEX 的纳米管的加入增强了 GelMA 的机械强度，但对其降解和溶胀率没有影响。扫描电子显微镜 (SEM) 图像显示了 GelMA 的多孔结构，该结构并未因 DEX 加载的纳米管 (HNTs/DEX) 的加入而显着改变。无论是否存在 HNT 或 HNT/DEX，所有 GelMA 制剂都显示出与 SHED 的细胞相容性 ( p < 0.05)。然而，在 GelMA 配方中添加 10% 的 HNT/DEX 后，观察到了最高的成骨细胞分化 ( p < 0.01)。DEX 7天的控释恢复了碱性磷酸酶和矿化的表达（p < 0.0001)在体外脂多糖 (LPS) 刺激的 SHED中。重要的是，体内数据显示，与不含 DEX 的配方相比，负载 DEX 的纳米管改性 GelMA（5.0% HNT/DEX 10%）在 6 周后导致骨形成增强（p < 0.0001），7 周后局部炎症反应最小。天。总之，我们的研究结果表明，工程化的负载 DEX 的纳米管改性水凝胶可能具有在炎症条件下触发原位矿化组织再生的巨大潜力。