金属有机框架复合物表面改性聚醚醚酮骨移植材料的研究

因意外或疾病导致的大段骨缺损修复一直是临床骨科的难点。聚醚醚酮（Polyetheretherketone，PEEK）因生物安全性好、与骨的弹性模量相近和X射线穿透性强等优点，成为临床大段骨缺损修复的重点研究材料。然而，PEEK呈生物惰性，植入体内后难以促进骨整合。因此，需要对其进行表面改性以提高骨整合性能。但影响骨整合的因素繁多如抑菌、抑炎、免疫调节、促血管生成和骨诱导等，且不同临床场景对材料的主要生物活性功能需求不同。因此，应结合临床需求开发多功能生物活性PEEK，从而提高PEEK在不同临床场景大段骨缺损修复下的骨整合能力。

金属有机框架（Metal-organic frameworks, MOFs）是由金属中心离子和有机配体组成的化合物，部分MOFs因具有一定的生物安全性、比表面积高和孔体积大等特点，被用于药物的装载及递送。本文提出基于MOFs结构中的金属中心离子、有机配体和所载药物，开发满足临床需求的多功能生物活性物质，并利用其对PEEK进行表面改性，从而开发出满足具体临床大段骨缺损修复需求的多功能生物生活PEEK。

首先，证实利用不同MOFs和药物开发满足不同临床需求的多功能生物活性物质策略的可行性。首先选取含有促进骨生长的Mg²⁺的Mg-MOF-74加载具有镇痛和抑炎功能的酮洛芬（Ketoprofen, KET），制备出KET@Mg-MOF-74。体外细胞研究发现KET@Mg-MOF-74在Mg²⁺和KET的协同作用下可达到镇痛、促骨生长和抑炎的效果。进而选取具有促骨生长、抑炎和抗菌功能的Zn²⁺和抗菌功能的二甲基咪唑（Dimethylimidazole，MeIm）构成的ZIF-8，加载具有抑炎和协同抗菌功能的塞来昔布（Celecoxib, CEL），制备出CEL@ZIF-8。抗菌实验和体外细胞实验证明了CEL@ZIF-8可通过Zn²⁺、MeIm和CEL，展示出良好的诱导成骨细胞分化、生长和成骨能力，及抑炎和抗菌效果。然后利用ZIF-8加载可促血管再生和骨再生及抑炎的二甲双胍（Metformin, MET）制备出MET@ZIF-8，以为后续开发应对不同临床骨缺损修复场景的PEEK奠定基础。研究证明了通过设计MOFs结构组成中的金属中心离子、有机配体和所载药物来开发满足不同临床需求的多功能生物活性物质的策略可行。

之后，提出利用磺化在PEEK表面构建三维网络多孔结构，然后通过超黏附性的多巴胺将MOFs引入PEEK表面和三维孔隙结构的表面改性思路。在优化了磺化时间、多巴胺溶液浓度和引入方式对PEEK形貌和结构的影响后，成功将CEL@ZIF-8和MET@ZIF-8引入PEEK的表面和孔隙，在PEEK表面构建了一种表面均匀分布且由外至内梯度分布的MOFs膜层结构。ZIF-8基多功能生物活性物质改性后的PEEK表面亲水性提高，且可在溶液中释放出Zn²⁺和药物。这为基于多功能MOFs生物活性物质改性PEEK的后续工作提供了技术经验。

最后，研究了上述多功能MOFs生物活性物质改性后的PEEK在临床大段骨缺损修复中的生物活性功能。通过体外细胞实验和体内动物实验研究，发现了CEL@ZIF-8改性后的PEEK即CEL@ZIF-8/PEEK在体内外均展示出良好的诱导成骨细胞分化和成骨、抑炎和调节骨免疫的功能；MET@ZIF-8改性后的PEEK即MET@ZIF-8/PEEK具有促血管再生、抑炎和促骨再生的功能。本文为针对不同临床场景大段骨缺损修复需求开发高骨整合性PEEK提供了新的方法。  

本文为针对临床大骨缺损多种修复需求开发新药物提供了新思路，实现了将MOFs生物活性物质引入PEEK表面的新技术，建立了不同临床大段骨缺损修复场景下提高PEEK骨整合性的新方法。本文所开发的CEL@ZIF-8/PEEK和MET@ZIF-8/PEEK，有望发展为新型医疗器械，为临床解决大段骨缺损这一难题提供有效支持。

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