含铜不锈钢对成骨作用的研究

Medical stainless steel is one of the most widely used medical implanting materials in clinical area, especially in orthopedics which requires the load bearing ability for the metallic medical materials. However, the inertness of medical stainless steel sometiems can not achieve a good bonding between bone tissue and implant, which may lead to the loosening and finally failure of the implant, especially for the implants which require long-term storage with load-bearing in human body. Better bonding between bone tissue and implant is crucial to the implants in clinical applications. Medical studies recently indicated that Cu ions could markedly promote the osteogenesis. Therefore, a creative idea proposed in this project is to fabricate a new stainless steel with proper addition of Cu in order to promote the osteogenesis during the implantation in bones. This can be achieved by constantly releasing the trace amount of Cu ions, which then promotes the osteogenesis on the surface of the Cu-bearing stainless steel and hence reaches a better bonding between bone tissue and the implant that needs long service time in human body.The measurement on the amount of Cu ions released from the Cu-bearing stainless steel, both in vitro and in vivo studies on the effect of Cu-bearing stainless steel on promoting osteogenesis will be conducted in this project in order to provide a sceientific proof for the application of Cu-bearing stainless steel in orthopaedics. Hence, the development of this Cu-bearing stainless steel is expected to go towards to the next generation of the biomaterials with bioactivities.

医用不锈钢是目前临床上应用最为广泛的医用植入材料之一，特别是在需要承力作用的骨科治疗中。然而医用不锈钢表现的生物惰性有时会导致植入后不能与周边骨组织牢固结合，可能引发松动而导致植入失效，特别是对需要长期存留于人体内，并需要承受较大载荷的骨科植入物。骨与植入物界面能否达到牢固的结合，对植入物能否在临床中发挥其功效至关重要。近期的医学研究表明，适量的铜离子对成骨过程有显著的促进作用。为此本项目创新性地提出发展具有促进成骨功能的含铜不锈钢骨内植入新材料，即通过含铜不锈钢中持续释放微量铜离子，促进植入物表面的成骨过程，进而达到需长期服役的不锈钢植入物与骨组织牢固结合的目的。本项目通过对含铜不锈钢中的铜离子释放测量、对成骨作用的体外实验和动物体内植入实验的研究探索，为含铜不锈钢在骨科临床中的应用提供科学依据，并推动医用不锈钢向自身具有生物活性的第二代生物材料的发展。

针对医用不锈钢金属材料自身生物惰性、无促成骨活性而导致的植入松动问题，项目负责人开发出一种新型的含铜不锈钢金属植入材料。这种含铜不锈钢是在317L型医用不锈钢（317L-SS）的化学成分基础上，在不锈钢冶炼过程中就加入适量的铜元素而制备得到的整体型含铜不锈钢（Cu-SS）。Cu-SS在液体和潮湿的环境中能够持续释放痕量的铜离子（Cu2+），进而发挥Cu2+的多种生物医学功能，赋予医用不锈钢材料生物活性，特别是促进成骨性能。本项目体外实验结果表明，Cu-SS所释放出的Cu2+能够促进成骨分化，主要是通过提高碱性磷酸酶（ALP）活性，提高成骨相关基因的表达（Col1a1, Opn, and Runx2），同时促进其表面成骨细胞的粘附与增殖，并且具有优异的细胞相容性。在体外实验的基础上，本项目开展了动物体内实验，制备了317L-SS、Cu-SS圆柱状植入物，植入大鼠股骨内，经过15天后处死动物取材，考察Cu-SS的成骨特性。体内结果进一步表明，与317L-SS相比，Cu-SS促进其周围骨组织的生长，增加骨密度，同时增强其与骨组织之间的结合力。因此Cu-SS无论是在体外还是动物体内实验均表现出优异的促进成骨性能。此外，体外细胞相容性实验以及动物体内组织相容性实验都表明Cu-SS具有生物相容性，无细胞毒性。通过离子释放速率测定，Cu-SS每日铜离子释放量为1.4 ppb/cm2远低于人体每日摄入铜的安全范围（2-3mg），从数据分析Cu-SS是具有生物相容性。另外，本项目还发现Cu-SS能够抑制植入后炎症因子TNF-α的释放，进而抑制术后炎症反应，这是本项目一项新的发现。因此，通过以上实验证明了含铜不锈钢具有优异的促成骨性能，同时没有生物毒性，有望在骨科临床中得到应用。