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具有生物活性元素诱导光热效应的 3D 打印支架用于骨肿瘤治疗。

3D-printed scaffolds with bioactive elements-induced photothermal effect for bone tumor therapy.

机构信息

State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

出版信息

Acta Biomater. 2018 Jun;73:531-546. doi: 10.1016/j.actbio.2018.04.014. Epub 2018 Apr 13.


DOI:10.1016/j.actbio.2018.04.014
PMID:29656075
Abstract

UNLABELLED: For treatment of bone tumor and regeneration of bone defects, the biomaterials should possess the ability to kill tumor cells and regenerate bone defect simultaneously. To date, there are a few biomaterials possessing such dual functions, the disadvantages, however, such as long-term toxicity and degradation, restrict their application. Although bioactive elements have been incorporated into biomaterials to improve their osteogenic activity, there is no report about elements-induced functional scaffolds for photothermal tumor therapy. Herein, the elements (Cu, Fe, Mn, Co)-doped bioactive glass-ceramic (BGC) scaffolds with photothermal effect and osteogenic differentiation ability were prepared via 3D-printing method. Moreover, the photothermal anti-tumor effect and osteogenic activity of these scaffolds were systematically investigated. The prepared elements-doped scaffolds possessed excellent photothermal performance, which displayed a trend, 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC, in this study. The final temperature of elements-doped scaffolds can be well controlled by altering the doping element categories, contents and laser power density. Additionally, the hyperthermia induced by 5Cu-BGC, 5Fe-BGC and 5Mn-BGC effectively killed tumor cells in vitro and inhibited tumor growth in vivo. More importantly, 5Fe-BGC and 5Mn-BGC scaffolds could promote rabbit bone mesenchymal stem cells (rBMSCs) adhesion, and the ionic products released from elements-doped scaffolds significantly stimulated the osteogenic differentiation of bone-forming cells. These results suggested that 5Fe-BGC and 5Mn-BGC scaffolds possessed promising potential for photothermal treatment of bone tumor and at the same time for stimulating bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds. STATEMENT OF SIGNIFICANCE: The major innovation of this study is that we fabricated the elements (Cu, Fe, Mn, Co)-doped bioactive scaffolds via 3D printing technique and found that they possess distinct photothermal performance and osteogenic differentiation ability. To the best of our knowledge, there is no report about elements-doped scaffolds for photothermal therapy of bone tumor. This is an important research advance by combining the photothermal effect and osteogenic differentiation activity of bioactive elements in the scaffold system for potential bone tumor therapy and bone reconstruction. We optimized the elements-doped scaffolds and found the photothermal effect of elements-doped scaffolds (5Cu-BGC, 5Fe-BGC, 5Mn-BGC) could effectively kill tumor cells in vivo. The photothermal performance of elements-doped scaffolds follows a trend: 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC > BGC. Compared to traditional nano-sized photothermal agents, bioactive elements-induced functional scaffolds have better biosecurity and bioactivity. Furthermore, 5Fe-BGC and 5Mn-BGC scaffolds displayed excellent bone-forming activity by stimulating the osteogenic differentiation of bone-forming cells. The major significance of the study is that the elements-doped bioactive glass-ceramics (5Fe-BGC, 5Mn-BGC) have great potential to be used as bifunctional scaffolds for photothermal tumor therapy and bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.

摘要

目的:为了治疗骨肿瘤和骨缺损的再生,生物材料应具有同时杀死肿瘤细胞和再生骨缺损的能力。迄今为止,只有少数几种生物材料具有这种双重功能,但长期毒性和降解等缺点限制了它们的应用。尽管已经将生物活性元素掺入生物材料中以提高其成骨活性,但尚无关于元素诱导的功能支架用于光热肿瘤治疗的报道。在此,通过 3D 打印方法制备了具有光热效应和成骨分化能力的元素(Cu、Fe、Mn、Co)掺杂生物活性玻璃陶瓷(BGC)支架。此外,系统研究了这些支架的光热抗肿瘤作用和成骨活性。所制备的元素掺杂支架具有优异的光热性能,在本研究中,5Cu-BGC>5Fe-BGC>5Mn-BGC>5Co-BGC。可以通过改变掺杂元素的种类、含量和激光功率密度来很好地控制元素掺杂支架的最终温度。此外,5Cu-BGC、5Fe-BGC 和 5Mn-BGC 诱导的热疗在体外有效杀死肿瘤细胞并抑制体内肿瘤生长。更重要的是,5Fe-BGC 和 5Mn-BGC 支架可以促进兔骨髓间充质干细胞(rBMSCs)的黏附,并且从元素掺杂支架中释放的离子产物显著刺激成骨细胞的成骨分化。这些结果表明,5Fe-BGC 和 5Mn-BGC 支架具有用于骨肿瘤光热治疗的潜在应用,同时可刺激骨再生,通过将双功能生物活性离子与组织工程支架相结合,为骨肿瘤的治疗提供了一种智能策略。

意义:本研究的主要创新之处在于,我们通过 3D 打印技术制备了元素(Cu、Fe、Mn、Co)掺杂的生物活性支架,并发现它们具有不同的光热性能和成骨分化能力。据我们所知,目前尚无关于用于骨肿瘤光热治疗的元素掺杂支架的报道。这是通过将生物活性元素的光热效应和成骨分化活性结合在支架系统中用于潜在的骨肿瘤治疗和骨重建的重要研究进展。我们优化了元素掺杂支架,并发现元素掺杂支架(5Cu-BGC、5Fe-BGC、5Mn-BGC)的光热效应可有效杀死体内肿瘤细胞。元素掺杂支架的光热性能呈以下趋势:5Cu-BGC>5Fe-BGC>5Mn-BGC>5Co-BGC>BGC。与传统的纳米级光热剂相比,生物活性元素诱导的功能支架具有更好的生物安全性和生物活性。此外,5Fe-BGC 和 5Mn-BGC 支架通过刺激成骨细胞的成骨分化表现出优异的成骨活性。该研究的主要意义在于,元素掺杂生物活性玻璃陶瓷(5Fe-BGC、5Mn-BGC)具有作为光热肿瘤治疗和骨再生的双功能支架的巨大潜力,通过将双功能生物活性离子与组织工程支架相结合,为骨肿瘤的治疗提供了一种智能策略。

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