Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, Michigan 48109, United States.
Department of Physiology and Pathology, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), 1680 Humaitá Street, Araraquara, Sao Paulo 14801-903, Brazil.
ACS Appl Bio Mater. 2021 Sep 20;4(9):6993-7006. doi: 10.1021/acsabm.1c00620. Epub 2021 Aug 27.
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 and . 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 ( < 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 ( < 0.01). The controlled release of DEX over 7 days restored the expression of alkaline phosphatase and mineralization ( < 0.0001) in lipopolysaccharide (LPS)-stimulated SHEDs . Importantly, data revealed that DEX-loaded nanotube-modified GelMA (5.0% HNT/DEX 10%) led to enhanced bone formation after 6 weeks ( < 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 mineralized tissue regeneration under inflammatory conditions.
能够通过在组织炎症下局部呈现治疗药物来扩增内源性祖细胞的再生能力的多功能水凝胶系统的工程化是硬组织再生有效策略转化的核心。在这里，我们将具有抗炎和矿化能力的多效药物地塞米松（DEX）加载到铝硅酸盐粘土纳米管（埃洛石粘土纳米管（HNTs））中，以基于光交联明胶甲基丙烯酰（GelMA）水凝胶来构建可注射的多功能药物输送系统。具体来说，分析了一系列基于 GelMA 配方的水凝胶，这些配方含有不同量的负载 DEX 的纳米管，以研究其物理化学和机械性能以及 DEX 释放的动力学，以及与人类脱落乳牙间充质干细胞（SHEDs）的相容性。通过测定和来确定工程水凝胶的抗炎反应和矿化潜力。FTIR 分析证实了 DEX 与 HNTs 的结合。负载 DEX 的纳米管的掺入增强了 GelMA 的机械强度，而对其降解和溶胀比没有影响。扫描电子显微镜（SEM）图像显示了 GelMA 的多孔结构，而负载 DEX 的纳米管（HNTs/DEX）的掺入并没有显著改变其结构。所有 GelMA 配方均表现出与 SHEDs 的细胞相容性（ < 0.05），无论存在 HNTs 还是 HNTs/DEX。然而，在 GelMA 配方中添加 HNT/DEX 10%时，观察到最高的成骨细胞分化（ < 0.01）。7 天内 DEX 的控制释放恢复了脂多糖（LPS）刺激的 SHEDs 中碱性磷酸酶和矿化的表达（ < 0.0001）。重要的是，数据表明，与不含 DEX 的制剂相比，载有 DEX 的纳米管修饰的 GelMA（5.0%HNT/DEX 10%）在 6 周后导致骨形成增强（ < 0.0001），并且在 7 天后具有最小的局部炎症反应。总的来说，我们的研究结果表明，所构建的载有 DEX 的纳米管修饰的水凝胶在炎症条件下可能具有引发矿化组织再生的巨大潜力。
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