CN115197693A - 一种nir-ⅱ区发光的核壳结构纳米粒子及其制备方法和应用 - Google Patents
一种nir-ⅱ区发光的核壳结构纳米粒子及其制备方法和应用 Download PDFInfo
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- CN115197693A CN115197693A CN202110382982.5A CN202110382982A CN115197693A CN 115197693 A CN115197693 A CN 115197693A CN 202110382982 A CN202110382982 A CN 202110382982A CN 115197693 A CN115197693 A CN 115197693A
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Abstract
本发明公开一种NIR‑Ⅱ区发光的核壳结构纳米粒子，该核壳结构纳米粒子以稀土配合物为内核，以无机钙磷矿化物为外壳，内核和外壳通过硅氧烷共价键键合；所述纳米粒子的平均粒径为20‑200nm，所述内核的平均粒径为10‑50nm。该纳米粒子中的内核在NIR‑Ⅱ区具有良好的荧光发光性能，外壳则是制备骨修复材料的原料。以纳米粒子为原料制备的骨修复材料，具有良好的生物相容性，荧光发光团在其中可以超均相分布，且性能稳定，能够实现厘米级深度生物活体成像，且荧光成像对比度高且保真，能够准确示踪骨修复材料的降解过程。同时，该核壳结构纳米粒子的制备过程简单易行，所用原料来源广泛，可工业化生产，具有良好的应用前景。
Description
技术领域
本发明涉及生物医用材料技术领域。更具体地，涉及一种NIR-Ⅱ区发光的核壳结构纳米粒子及其制备方法和应用。
背景技术
与常规断层扫描技术如计算机断层扫描(computed tomography，CT)、正电子发射断层扫描(positron emission tomography，PET)和核磁共振成像(magnetic resonanceimaging，MRI)有限的空间分辨率和长时间采集导致无法实时、动态可视化等弱点相比，近红外“第二透明窗口”(The Second Near-Infrared Window，NIR-II)(1000-1700nm)活体荧光成像技术具有快速反馈、多光子通道、高灵敏度、高分辨率以及无电离辐射等优点。同时与传统可见光(400-650nm)和近红外第一窗口(NIR-I，650-950nm)荧光发射波段相比，生物体自身组织(如血管，皮肤，脂肪，黄素，卟啉和胶原等)，以及外源性食品对光子吸收和散射作用较大。根据光子输运平均自由程(Transport Mean Free Path,TMFP)公式：
TMFP＝1/(μs′+μa)，
μs′—组织散射减少系数，μa—是组织吸收系数
可见光和NIR-I波段激发发射荧光对生物组织的穿透深度较低(<5mm)，造成成像空间分辨率低(～1000μm)和时间分辨率低(～1000ms)，而且生物组织在该波段自发荧光强，严重干扰生物成像信号的输出。而在NIR-II区域，光子吸收和散射作用远远小于可见光和NIR-I区域，且该波段生物组织自发荧光可近似忽略，具有信噪比高，灵敏度高，图像对比度高、高保真。有文献报道NIR-II荧光探针生物成像技术能够达到前所未有的组织穿透成像深度(1.8cm)。
脊椎动物硬组织(骨和软骨)在遭遇环境机械外力损伤、高低温烫伤冻伤、化学品灼伤，以及组织内部肿瘤癌变切除后会造成组织缺损，如果不及时利用合适的生物材料填充、遮蔽形成隔离体系，毛细血管渗血、成纤维细胞长入、环境中细菌、病毒、支原体等微生物侵入对组织再生修复极为不利，更严重者可能引发组织截肢，甚至死亡。目前，自体骨由于其卓越的自适配性、骨诱导性和骨传导性，是临床上缺损骨修复的“金标准”。但是其数量有限、多次手术以及取骨部位疼痛限制了其广泛应用。此外，同种异体骨移植物也被用于骨缺损再生修复治疗，但是疾病传播、异体免疫排斥和数量有限也限制了其应用。人工方法利用骨组织工程干预骨组织再生修复，涉及支架材料、细胞和生物因子的整合，通过向细胞提供力学支撑、地貌引导和生化信号等适当组合来模拟骨组织细胞外基质以促进缺损骨组织的再生生长。支架(scaffold)是骨组织工程技术的核心与载体，scaffold要尽可能模骨组织细胞外基质的组成、结构和其他特性。骨组织细胞外基质能够为前成骨细胞、成骨细胞和破骨细胞提供力学结构支撑、信号引导以及O2、营养物质和代谢废物扩散和对流的介质。在骨组织再生修复过程中，scaffold还应该具有生物降解性能，降解留下的空间能够为成骨细胞和破骨细胞的贴附生长、增殖以及干细胞的分化提供内向生长空间，进一步促进细胞分泌成骨生长因子和生物分子到周围微环境中，在微观上构建原生骨组织细胞外基质，宏观上实现缺损骨组织的再生修复。通过NIR-II区荧光可视化scaffold在活体内的生物降解过程，可以在体外更好的设计制造scaffold，促使其在体内的降解速率与新骨生长速率匹配，达到最优的骨缺损再生修复效果，并且可以做到个性化个体骨缺损再生治疗，减少替代和优化实验动物的使用。
王艳芹等人采用化学交联技术和循环冷冻-解冻技术相结合,制备了Au纳米簇/羟基磷灰石/聚乙烯醇复合水凝胶材料骨修复体备选材料，利用Au纳米簇赋予了其近红外荧光示踪信号。中国专利CN1096029450A通过在骨水泥内添加适量表面修饰后的Ag2S量子点组分，发明了一种NIR-II区荧光可监控降解型骨水泥，赋予修复材料体系在近红外显影的功能，用于骨材料活体内降解吸收的跟踪。但是Au纳米簇荧光探针极不稳定，不易降解，在体内使用时易于团聚，并造成正常组织富集。Ag2S荧光探针亲水性和光学稳定性差，表面聚乙二醇功能化后，量子产率降低且初次曝光200s后，荧光产率降为初始的50％，且该方法属于物理混合，成像颗粒与功能颗粒之间存在明显界面，缺乏有效的化学键力以实现Ag2S量子点的可靠固定及均匀分布。
因此，需要提供一种能够均匀分布、光学和化学响应稳定、与人体骨组织具有生物相容性，且在NIR-II区荧光示踪骨修复材料降解过程的材料。
发明内容
本发明的一个目的在于提供一种NIR-Ⅱ区发光的核壳结构纳米粒子，该纳米粒子具有核壳结构，作为内核的稀土有机配合物在NIR-Ⅱ区发光，与CaP外壳通过硅氧烷共价键键合，结构稳定，光学和化学性能稳定，且与骨修复材料相容性好，分布均匀。
本发明的第二个目的在于提供一种NIR-Ⅱ区发光的核壳结构纳米粒子的制备方法。
本发明的第三个目的在于提供一种包括上述NIR-Ⅱ区发光的核壳结构纳米粒子的骨修复材料。
本发明的第四个目的在于提供上述NIR-Ⅱ区发光的核壳结构纳米粒子在骨修复中的应用
为达到上述目的，本发明采用下述技术方案：
一种NIR-Ⅱ区发光的核壳结构纳米粒子，该核壳结构纳米粒子以稀土有机配合物为内核，以无机钙磷矿化物为外壳，内核和外壳通过硅氧烷共价键键合；
其中，所述纳米粒子的平均粒径为20-200nm，所述内核的平均粒径为10-50nm。
本发明中NIR-Ⅱ区指的是近红外第二透明窗口，对应波长范围为1000-1700nm。
本发明中NIR-Ⅱ区发光的核壳结构纳米粒子的内核和外壳通过硅氧烷共价键键合，外壳为内核提供稳定的光、热、化学保护，该纳米粒子结构稳定。
作为内核的稀土有机配合物能够在NIR-Ⅱ区发射荧光，荧光信号信噪比高、灵敏度高、成像对比度高且保真，可用于各类骨修复材料的跟踪，监控材料的降解吸收代谢速率，实现体外设计优化骨再生修复材料。
作为外壳的无机钙磷矿化物生物仿生人体硬组织的无机成份，通常作为制备骨修复材料的原料，用本发明中的NIR-Ⅱ区发光的核壳结构纳米粒子来制备骨修复材料时，作为荧光材料的内核在骨修复材料中的分布均匀，荧光示踪能够更加真实的反映骨修复材料的降解过程。
优选地，所述稀土中心离子为Eu3+、Tb3+、Sm3+、Dy3+、Nd3+、Ho3+、Er3+、Tm3+、Pr3+、Ce3+、Pm3+、Gd3+、Sc3+、Y3+中的一种。
优选地，所述的配体包括邻菲罗啉、二乙烯三胺五乙酸、4,4,4-三氟-1-(2-萘基)-1,3-丁二酮、4,4,5,5,5-五氟-1-(2-萘基)-1,3-丁二酮、4-甲氧基联苯甲酰三氟丙酮、噻吩甲酰三氟丙酮、1,4,7,10-四氮杂环十二烷-1,4,7,10-四羧酸、4-(1,3,5-间苯甲酰基)-(3-甲基-1苯基-2-吡唑啉-5酮)、六氟乙酰丙酮中的一种或多种。
在本发明的稀土有机配合物中配体分子吸收激发光能量后，能将能量从配体分子激发态无辐射跃迁的传递至中心离子的发射能级，可以定向敏化中心镧系离子，得到更高的量子发射效率，更长的荧光寿命，以及更好的荧光发射发光性能，实现NIR-Ⅱ区发光。
优选地，所述无机钙磷矿化物选自磷酸氢钙、缺钙磷灰石、磷酸八钙、无定形磷酸钙、碳酸根掺杂磷灰石中的一种或几种。
本发明中作为纳米粒子外壳的无机钙磷矿化物是制备骨修复材料的原料，稳定的核壳结构保证了制备得到的骨修复材料中荧光分子稀土有机配合物的超均相分布，提高了内核稀土有机配合物的光、热和化学稳定性，以及骨修复材料用于生物活体体内的生物相容性。
本发明第二个方面提供了上述NIR-Ⅱ区发光的核壳结构纳米粒子的制备方法，包括如下步骤：
(1)20-100℃下，惰性气体环境中，将稀土有机配合物加入至四氢呋喃和水的混合溶液中，加入NaH；滴加入硅烷偶联剂，反应后得硅烷偶联功能化的稀土有机配合物；
(2)向pH为6.5-13.5的无机钙磷矿化物过饱和缓冲液中加入硅烷偶联功能化的稀土有机配合物，得到反应液；反应过程中维持反应液pH在6.5-13.5之间；结束后，对反应液进行固液分离，得固体，用去离子水、乙醇依次洗涤固体，干燥，得到NIR-Ⅱ区发光的核壳结构纳米粒子。
优选地，步骤(1)中滴加入的硅烷偶联剂与稀土有机配合物的质量比为0.001:1～10:1；滴加入的硅烷偶联剂与加入NaH的质量比为100:1。
所述硅烷偶联剂包括但不限于，例如，十二烷基三甲氧基硅烷、乙烯基三乙氧基硅烷、3-氨基丙基三乙氧基硅烷、双(γ-三甲基甲硅烷基丙基)胺、γ-(2,3-环氧丙氧基)丙基三甲氧基硅烷、异氰酸丙基三乙氧基硅烷等。
优选地，步骤(1)中反应是在20-100℃下，反应20min-48h；惰性气体选自氮气或氩气。
优选地，步骤(2)反应液中硅烷偶联功能化的稀土有机配合物的浓度为0.01～1mg/mL。
优选地，步骤(2)中反应是在20-100℃下，反应1min-7天；反应过程中的连续搅拌速率为0～1000rpm。
步骤(2)的反应过程中，若温度较高，同时伴随着搅拌操作，则反应较快，在几分钟内便可完成；若温度较低，且无进行搅拌操作，则反应较慢，需要几天的时间才能完成。
进一步优选地，步骤(2)中的反应是在90-100℃下，反应1min-8h，反应过程中的连续搅拌速率为200～1000rpm。
在具体的实施方式中，步骤(2)中的固液分离过程采用的是减压抽滤或离心沉淀法；洗涤次数为1-5次，干燥采用的是冷冻干燥法、常压或真空烘干法或喷雾干燥法中的一种。
需要说明的是，步骤(2)中反应过程中维持反应液pH在6.5-13.5的方法，与制备无机钙磷矿化物过饱和缓冲液过程中使用的调节pH的溶液种类有关。
若制备无机钙磷矿化物过饱和缓冲液过程中使用的是氨水、氢氧化钠、氢氧化钾、氢氧化钙等碱性溶液来调节pH，则步骤(2)中可以通过不断加入碱溶液或HCl-Tris缓冲液、磷酸盐缓冲液、杜尔贝科磷酸盐缓冲液等缓冲液来维持pH；
若制备无机钙磷矿化物过饱和缓冲液过程中使用的是HCl-Tris缓冲液、磷酸盐缓冲液、杜尔贝科磷酸盐缓冲液等缓冲液来调节pH，则在步骤(2)一般不需要加入额外的试剂来维持pH。
本发明还提供了步骤(1)中稀土有机配合物的制备包括如下步骤：将配体溶解至无水乙醇中，调节pH至7-9，搅拌状态下加入稀土离子盐的乙醇溶液；加热回流反应30min-24h，冷却至室温，过滤，得到稀土有机配合物。
优选地，制备稀土有机配合物的反应过程中稀土离子和配体的摩尔比为1:(1～4)。
优选地，制备稀土有机配合物过程中调节pH使用的是碱溶液，碱溶液选自氢氧化钠溶液、氢氧化钾溶液、氢氧化钙溶液、氨水中的至少一种；碱溶液的浓度为0.001mol/L-10mol/L。
本发明还提供了步骤(2)中过饱和无机钙磷矿化物缓冲溶液的一种可能的制备方法，包括以下步骤：室温下，将可溶性钙盐和可溶性磷酸盐溶于水中，搅拌混匀，达到过饱和状态，然后调节其pH至6.5-13.5。
优选地，在制备过饱和无机钙磷矿化物缓冲溶液过程中，用于调节pH的溶液包括但不限于，例如氨水、氢氧化钠溶液、氢氧化钾溶液、氢氧化钙溶液、HCl-Tris缓冲液、磷酸盐缓冲液或杜尔贝科磷酸盐缓冲液。
所述可溶性钙盐包括但不限于氯化钙、硝酸钙、乙酸钙、葡萄糖酸钙、磷酸二氢钙、碳酸氢钙、硫酸氢钙、亚硫酸氢钙、次氯酸钙、溴化钙、碘化钙、氯酸钙、高氯酸钙、高锰酸钙等。
所述可溶性磷酸盐包括但不限于磷酸氢二铵、磷酸氢二钠、磷酸氢二钾、磷酸二氢钠、磷酸二氢钾、磷酸钠、磷酸钾等。
优选地，在制备过饱和无机钙磷矿化物缓冲溶液过程中，加入的钙元素和磷元素的摩尔比为1:1～3:1。
本发明还提供了一种骨修复材料，包括有上述NIR-Ⅱ区发光的核壳结构纳米粒子。
优选地，所述骨修复材料为可降解的骨修复材料；
优选地，所述骨修复材料选自骨水泥、骨支架、骨表面涂层、生物陶瓷。
本发明同时提供了上述NIR-Ⅱ区发光的核壳结构纳米粒子在骨修复中的应用。
优选地，所述应用过程包括可降解骨修复材料的荧光降解过程、新骨形成于可降解骨修复材料之间的界面迁移。
上述核壳结构纳米粒子的内核稀土有机配合物在NIR-Ⅱ区能够发光，外壳无机钙磷矿化物则是骨修复材料的原料，因此，含有上述NIR-Ⅱ区发光的核壳结构纳米粒子的骨修复材料，具有良好的生物相容性，光、热和化学稳定性好，且荧光发光团在骨修复材料中可以超均相分布，能够准确示踪骨修复材料的降解过程。
本发明的有益效果如下：
本发明提供一种以稀土有机配合物为内核，以无机钙磷矿化物为外壳的核壳结构纳米粒子，其中内核和外壳通过硅氧烷共价键键合，稀土有机配合物在NIR-Ⅱ区具有良好的荧光发光性能，无机钙磷矿化物则是制备骨修复材料的原料。以该核壳结构纳米粒子为原料制备得到的骨修复材料，具有良好的生物相容性，荧光发光团在其中可以超均相分布，且性能稳定，能够实现厘米级深度生物成像，且荧光成像对比度高且保真，能够准确示踪骨修复材料的降解过程。
同时，该核壳结构纳米粒子的制备过程简单易行，所用原料来源广泛，可工业化生产，具有良好的应用前景。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出实施例1中所述方法制备的NIR-II区发光的核壳结构纳米粒子激发和发射光谱图。
图2示出实施例2中所述方法制备的NIR-II区发光的核壳结构纳米粒子的扫描电子显微镜图。
图3示出实施例3中所述方法制备的NIR-II区发光的核壳结构纳米粒子的红外谱图。
图4示出检测例中NIR-II区发光的核壳结构纳米粒子与L929细胞连续共培养7天的细胞增殖结果。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
将0.03mol的4,4,4-三氟-1-(2-萘基)-1,3-丁二酮和0.01mol的邻菲罗琳(phen)配体分子溶解在2000mL的无水乙醇中，使用适量的10mol/L氢氧化钠将其pH调节为9。在搅拌状态下加入ErCl3乙醇溶液(含有ErCl3的量为0.01mol)，混匀后加热回流反应24h，冷却至室温，过滤，得到Er3+配合物，结构式如下：
称取上述制备得到的Er3+配合物0.1g，溶解在四氢呋喃和水的混合溶液中，在100℃，N2气体保护下，滴加1g的异氰酸丙基三乙氧基硅烷，加入0.01gNaH，连续反应48h，得到硅烷偶联功能化的Er3+配合物。
室温下，称取0.01g葡萄糖酸钙和0.006g磷酸氢二钠，加入至100mL去离子水中，充分搅拌混合，使用杜尔贝科磷酸盐缓冲液调节其pH在13.5，得到无机钙磷矿化物过饱和缓冲液。
称取0.1g的硅烷偶联功能化的Er3+配合物，加入至100mL无机钙磷矿化物过饱和缓冲液中。在100℃温度下，以1000rpm的速度搅拌反应1min，得到白色乳液。然后将白色乳液减压抽滤，得到的白色固体用去离子水、乙醇依次洗涤5次，然后将白色固体冷冻干燥，得到NIR-II区荧光可视化全生物相容性降解型纳米粒子。该纳米粒子的激发和发射光谱如图1所示，可见该纳米粒子在NIR-Ⅱ区(1000-1700nm)具有较强的荧光发射。
实施例2
将0.01mol的二乙烯三胺五乙酸配体分子溶解在10mL的无水乙醇中，使用适量的0.001mol/L氢氧化钾将其pH调节为7。在搅拌状态下加入GdCl3-乙醇溶液(含有GdCl3的量为0.01mol)，混匀后加热回流反应30min，冷却至室温，过滤，得到Gd3+配合物，结构式如下：
称取上述制备得到的Gd3+配合物1g，溶解在四氢呋喃和水的混合溶液中，在20℃，N2气体保护下，加入0.001g的异氰酸丙基三乙氧基硅烷，加入0.00001gNaH，连续反应20min，得到硅烷偶联功能化的Gd3+配合物。
室温下，称取0.01g葡萄糖酸钙和0.006g磷酸氢二钠，加入至100mL去离子水中，充分搅拌混合，使用杜尔贝科磷酸盐缓冲液调节其pH在6.5，得到无机钙磷矿化物过饱和缓冲液。
称取0.01g的硅烷偶联功能化的Gd3+配合物，加入至1000mL无机钙磷矿化物过饱和缓冲液中。在20℃温度下，以0rpm的速度反应7天，得到白色乳液。然后将白色乳液减压抽滤，得到的白色固体用去离子水、乙醇依次洗涤5次，然后将白色固体冷冻干燥，得到NIR-II区荧光可视化全生物相容性降解型纳米粒子。该纳米粒子扫描电子显微镜如图2所示，该纳米粒子的平均粒径为100nm，其中内核的平均粒径为20nm。
实施例3
将0.01mol的噻吩甲酰三氟丙酮和0.03mol的邻菲罗琳(phen)配体分子溶解在50mL的无水乙醇中，使用适量的0.001mol/L氢氧化钾将其pH调节为7。在搅拌状态下加入NdCl3-乙醇溶液(含有NdCl3的量为0.01mol)，混匀后加热回流反应8h，冷却至室温，过滤，得到Nd3+配合物，结构式如下：
称取上述制备的Nd3+配合物0.5g，溶解在四氢呋喃和水的混合溶液中。在37℃温度，N2气体保护下，滴加1g的十二烷基三甲氧基硅烷，加入0.01gNaH，连续反应4h，即得到硅烷偶联功能化的Nd3+配合物。
室温下，称取0.3g的氯化钙和0.18磷酸钠加入到1000mL去离子水，充分搅拌混合，以饱和氨水调节混合液的pH在7.80，得到无机钙磷矿化物过饱和缓冲液。
称取0.2g的硅烷偶联功能化Nd3+配合物，加入至1000mL无机钙磷矿化物过饱和缓冲液中。在90℃温度下，200rpm搅拌下持续反应8h，得到白色乳液。然后将白色乳液减压抽滤，得到的白色固体用去离子水、乙醇依次洗涤5次，然后将白色固体冷冻干燥，得到NIR-II区荧光可视化全生物相容性降解型纳米粒子。Nd3+配合物的红外谱图如图3所示，可见Nd3+与配体形成了稳定的Nd3+配合物。
测试例
检测实施例3备得到的核壳结构纳米粒子的生物相容性和细胞毒性
以L929细胞为测试细胞，在增殖培养基(DMEM，含有10％胎牛血清)，在37℃，100％相对湿度和5％CO2培养条件下。细胞培养基每二天更换一次。细胞增殖至其对数生长期后，将细胞用磷酸盐缓冲液(PBS)冲洗，用0.25％胰蛋白酶消化吹打分散，以细胞浓度5000个/孔种植至48孔细胞培养板，贴壁生长24h后备用。
将实施例3制备得到的核壳结构纳米粒子灭菌处理后，超声分散在完全培养基中，使其浓度为3mg/mL。取50μL每孔纳米粒子悬液加入至上述48孔细胞培养板中，连续培养7天，每24小时更换培养基。使用光学显微镜连续观察细胞的增殖情况，结果如图4所示，可见细胞在7天之内连续增殖，说明本发明实施例3制备得到的NIR-Ⅱ区发光的核壳结构纳米粒子具有良好的生物安全性，基本无细胞毒性。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
Claims (10)
1.一种NIR-Ⅱ区发光的核壳结构纳米粒子，其特征在于，该核壳结构纳米粒子以稀土有机配合物为内核，以无机钙磷矿化物为外壳，内核和外壳通过硅氧烷共价键键合；
其中，所述纳米粒子的平均粒径为20-200nm，所述内核的平均粒径为10-50nm。
2.根据权利要求1所述的核壳结构纳米粒子，其特征在于，所述稀土有机配合物的中心离子为Eu3+、Tb3+、Sm3+、Dy3+、Nd3+、Ho3+、Er3+、Tm3+、Pr3+、Ce3+、Pm3+、Gd3+、Sc3+、Y3+中的一种。
3.根据权利要求1所述的核壳结构纳米粒子，其特征在于，所述的稀土有机配合物的配体分子包括邻菲罗啉、二乙烯三胺五乙酸、4,4,4-三氟-1-(2-萘基)-1,3-丁二酮、4,4,5,5,5-五氟-1-(2-萘基)-1,3-丁二酮、4-甲氧基联苯甲酰三氟丙酮、噻吩甲酰三氟丙酮、1,4,7,10-四氮杂环十二烷-1,4,7,10-四羧酸、4-(1,3,5-间苯甲酰基)-(3-甲基-1苯基-2-吡唑啉-5酮)、六氟乙酰丙酮中的一种或多种。
4.根据权利要求1所述的核壳结构纳米粒子，其特征在于，所述无机钙磷矿化物选自磷酸氢钙、缺钙磷灰石、磷酸八钙、无定形磷酸钙、碳酸根掺杂磷灰石中的一种或几种。
5.如权利要求1-4任一所述NIR-Ⅱ区发光的核壳结构纳米粒子的制备方法，其特征在于，包括如下步骤：
(1)20-100℃下，惰性气体环境中，将稀土有机配合物加入至四氢呋喃和水的混合溶液中，加入NaH；滴加入硅烷偶联剂，反应后得硅烷偶联功能化的稀土有机配合物；
(2)向pH为6.5-13.5的无机钙磷矿化物过饱和缓冲液中加入硅烷偶联功能化的稀土有机配合物，得反应液；反应过程中维持反应液pH在6.5-13.5之间；结束后，对反应液进行固液分离，得固体，用去离子水、乙醇依次洗涤固体，干燥，得到NIR-Ⅱ区发光的核壳结构纳米粒子。
6.根据权利要求5所述的制备方法，其特征在于，步骤(1)中，滴加入的硅烷偶联剂与稀土有机配合物的质量比为0.001～10:1；优选地，步骤(2)反应液中硅烷偶联功能化的稀土有机配合物的浓度为0.01～1mg/mL。
7.根据权利要求5所述的制备方法，其特征在于，步骤(1)中稀土有机配合物的制备包括如下步骤：
将配体分子溶解至无水乙醇中，调节pH至7-9，搅拌状态下加入稀土离子盐的乙醇溶液；加热回流反应30min-24h，冷却至室温，过滤，得稀土有机配合物。
8.一种骨修复材料，其特征在于，所述骨修复材料包括有如权利要求1-4所述NIR-Ⅱ区发光的核壳结构纳米粒子；
优选地，所述骨修复材料为可降解的骨修复材料；
优选地，所述骨修复材料选自骨水泥、骨支架、骨表面涂层、生物陶瓷。
9.一种如权利要求1-4所述NIR-Ⅱ区发光的核壳结构纳米粒子在骨修复中的应用。
10.根据权利要求9所述的应用，其特征在于，所述应用过程包括可降解骨修复材料的荧光降解过程，新骨形成与可降解骨修复材料之间的界面迁移。
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