Aspirin synergizes with mineral particle-coated macroporous scaffolds for bone regeneration through immunomodulation.
Aspirin synergizes with mineral particle-coated macroporous scaffolds for bone regeneration through immunomodulation.
复制标题
阿司匹林与矿物颗粒包覆的大孔支架通过免疫调节协同促进骨再生。
作者：
Su N;Villicana C;Zhang C;Lee J;Sinha S;Yang A;Yang F
理由：矿物颗粒由于其骨传导和骨诱导特性而被广泛用于骨组织工程支架。尽管矿物质颗粒有很多好处，但它会引起不良炎症和随后的骨吸收。阿司匹林（Asp）是一种廉价且广泛使用的抗炎药。本研究的目的是评估大孔支架中天冬氨酸和优化矿物颗粒涂层的协同效应，以加速临界尺寸骨缺损模型中的内源性骨再生并减少骨吸收。方法：使用四种常用的矿物颗粒，其成分不同（羟基磷灰石与磷酸三钙）和尺寸（纳米与微米）。将矿物颗粒涂覆在明胶微带 (μRB) 支架上。巨噬细胞 (Mφ) 在含有各种颗粒的明胶 µRB 支架上培养，并使用 PCR 和 ELISA 评估 Mφ 极化。还体外评估了来自 Mφ 的条件培养基对间充质干细胞 (MSC) 成骨的影响。然后将含有优化矿物颗粒的支架与不同剂量的天冬氨酸结合，以使用临界尺寸的颅骨缺损模型来评估诱导内源性骨再生的效果。进行体内表征和体外细胞研究，以阐明调整 Asp 剂量对 Mφ 极化、破骨细胞 (OC) 活性和 MSC 成骨的影响。结果：微米尺寸的磷酸三钙 (mTCP) 颗粒被认为在促进 M2 Mφ 极化和在 Mφ 条件培养基存在的情况下挽救基于 MSC 的骨形成方面是最佳的。当植入体内时，将 Asp 与 mTCP 涂层 µRB 支架结合，以剂量依赖性方式显着加速内源性骨形成。令人印象深刻的是，含有 20 µg 天冬氨酸的 mTCP 涂层 µRB 支架早在第 2 周就使临界大小的颅骨缺损几乎完全愈合，并且随后没有骨吸收。 Asp 在体内以剂量依赖性方式增强 M2 Mφ 极化、降低 OC 活性并促进 MSC 成骨。使用体外细胞研究进一步验证了这些结果。结论：在这里，我们证明天冬氨酸和矿物颗粒涂层的微带支架为通过免疫调节修复临界尺寸的颅骨缺损提供了一种有前途的疗法。领先的配方支持快速的内源性骨再生，无需外源细胞或生长因子，这使其对转化具有吸引力。我们的结果还强调了优化矿物质颗粒和天冬氨酸剂量以实现稳健的骨愈合的重要性，同时通过针对 Mφ 和 OC 避免骨吸收。
Rationale: Mineral particles have been widely used in bone tissue engineering scaffolds due to their osteoconductive and osteoinductive properties. Despite their benefits, mineral particles can induce undesirable inflammation and subsequent bone resorption. Aspirin (Asp) is an inexpensive and widely used anti-inflammatory drug. The goal of this study is to assess the synergistic effect of Asp and optimized mineral particle coating in macroporous scaffolds to accelerate endogenous bone regeneration and reduce bone resorption in a critical-sized bone defect model. Methods: Four commonly used mineral particles with varying composition (hydroxyapatite v.s. tricalcium phosphate) and size (nano v.s. micro) were used. Mineral particles were coated onto gelatin microribbon (µRB) scaffolds. Macrophages (Mφ) were cultured on gelatin µRB scaffolds containing various particles, and Mφ polarization was assessed using PCR and ELISA. The effect of conditioned medium from Mφ on mesenchymal stem cell (MSC) osteogenesis was also evaluated in vitro. Scaffolds containing optimized mineral particles were then combined with varying dosages of Asp to assess the effect in inducing endogenous bone regeneration using a critical-sized cranial bone defect model. In vivo characterization and in vitro cell studies were performed to elucidate the effect of tuning Asp dosage on Mφ polarization, osteoclast (OC) activity, and MSC osteogenesis. Results: Micro-sized tricalcium phosphate (mTCP) particles were identified as optimal in promoting M2 Mφ polarization and rescuing MSC-based bone formation in the presence of conditioned medium from Mφ. When implanted in vivo, incorporating Asp with mTCP-coated µRB scaffolds significantly accelerated endogenous bone formation in a dose-dependent manner. Impressively, mTCP-coated µRB scaffolds containing 20 µg Asp led to almost complete bone healing of a critical-sized cranial bone defect as early as week 2 with no subsequent bone resorption. Asp enhanced M2 Mφ polarization, decreased OC activity, and promoted MSC osteogenesis in a dosage-dependent manner in vivo. These results were further validated using in vitro cell studies. Conclusions: Here, we demonstrate Asp and mineral particle-coated microribbon scaffold provides a promising therapy for repairing critical-sized cranial bone defects via immunomodulation. The leading formulation supports rapid endogenous bone regeneration without the need for exogenous cells or growth factors, making it attractive for translation. Our results also highlight the importance of optimizing mineral particles and Asp dosage to achieve robust bone healing while avoiding bone resorption by targeting Mφ and OCs.
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