Department of Prosthodontics, Faculty of Odontology, Malmö University, Malmö, Sweden.
Department of Biomaterials, Institute of Clinical Sciences, Gothenburg University, Gothenburg, Sweden.
Clin Implant Dent Relat Res. 2018 Feb;20(1):82-91. doi: 10.1111/cid.12578. Epub 2017 Dec 28.
Osseointegration mechanisms are still not entirely understood.
The present pilot study aims at demonstrating the involvement of the immune system in the process of osseointegration around titanium implants, comparing bone healing in the presence and absence of a titanium implant.
Fifteen New Zealand White rabbits had one osteotomy performed at each of the distal femurs; on one side, no implant was placed (sham) and on the other side a titanium implant was introduced. Subjects were sacrificed at 10 and 28 days for gene expression analysis (three subjects each time point) and for decalcified qualitative histology (six subjects each time point). At 10 days, the three subjects for gene expression analysis were part of the six subjects for histology.
Gene expression analysis: at 10 days, ARG1 was significantly up-regulated around titanium, indicating an activation of M2-macrophages. At 28 days CD11b, ARG1, NCF-1, and C5aR1 were significantly up-regulated, indicating activation of the innate immune system, respectively M1-macrophages, M2-macrophages and group 2-innate lymphoid cells, neutrophils, and the complement system; on the other hand, the bone resorption markers RANKL, OPG, cathepsin K, and TRAP were significantly down-regulated around titanium.
at 10 days new bone formation is seen around both sham and titanium sites, separating bone marrow from the osteotomy/implant site; at 28 days no bone trabeculae is seen on the sham site, which is healing at the original cortical level, whereas around titanium implants, bone continues into organization of more mature cortical-like bone, forming a layer between the implant and the bone marrow.
The presence of a titanium implant during bone healing activates the immune system and displays type 2 inflammation, which is likely to guide the host-biomaterial relationship. At the same time, bone resorption is suppressed around titanium sites compared to sham sites after 4 weeks of implantation, suggesting a shift to a more pronounced bone forming environment. This suggests two important steps in osseointegration: identification of the titanium foreign body by the immune system and the development of a bone forming environment, that at tissue level translates into bone build-up on the titanium surface and can be perceived as an attempt to isolate the foreign body from the bone marrow space.
骨整合机制仍不完全清楚。
本初步研究旨在证明免疫系统参与钛种植体周围的骨整合过程，比较有和没有钛种植体时的骨愈合情况。
15 只新西兰白兔的双侧股骨远端各行 1 次截骨术；一侧不放置植入物（假手术），另一侧放置钛植入物。在 10 天和 28 天处死 3 只每个时间点的动物进行基因表达分析，6 只每个时间点进行脱钙定性组织学分析。在 10 天，3 只进行基因表达分析的动物为 6 只进行组织学分析的动物的一部分。
基因表达分析：在 10 天，ARG1 在钛周围显著上调，表明 M2 巨噬细胞被激活。在 28 天，CD11b、ARG1、NCF-1 和 C5aR1 显著上调，分别表明先天免疫系统、M1 巨噬细胞、M2 巨噬细胞和 2 型固有淋巴细胞、中性粒细胞和补体系统的激活；另一方面，钛周围的骨吸收标志物 RANKL、OPG、组织蛋白酶 K 和 TRAP 显著下调。
在 10 天，在 sham 和钛部位都可见新骨形成，将骨髓与截骨/植入部位分开；在 28 天， sham 部位未见骨小梁，正在愈合至原始皮质水平，而钛植入物周围的骨继续形成更成熟的皮质样骨，在植入物和骨髓之间形成一层。
在骨愈合过程中放置钛种植体可激活免疫系统并显示 2 型炎症，这可能指导宿主-生物材料关系。同时，与 sham 部位相比，钛植入物部位在植入后 4 周时骨吸收受到抑制，提示向更明显的成骨环境转变。这表明骨整合的两个重要步骤：免疫系统识别钛异物和形成成骨环境，在组织水平上转化为钛表面的骨形成，并可被视为试图将异物与骨髓空间隔离。
