成纤维细胞与人工关节周围骨溶解

人工关节无菌性松动的早期在X线片上表现为假体周围骨溶解,组织学研究发现骨水泥与骨组织界面之间或假体与骨组织之间始终存在纤维组织样假膜,假膜中有大量巨噬细胞和成纤维细胞.近年研究提示人工关节磨损颗粒激活巨噬细胞是导致假体周围骨溶解的起始因素,但成纤维细胞在促进假体周围骨溶解中也起到重要的作用.该文主要从人工关节周围组织中成纤维细胞促破骨细胞分化作用、成纤维细胞活化过程、细胞内信号传导等方面,就成纤维细胞在骨溶解发生中的生物学机制作一综述.     

人工关节无菌松动界膜中破骨细胞分化因子受体免疫阳性的多核巨细胞

人工关节置换术后最重要的并发症是假体周围骨溶解导致的假体无菌松动 ,松动的机理还不完全清楚。随着骨代谢研究的进展 ,调节破骨细胞形成和功能的肿瘤坏死因子家族 (ＴＮＦｓ)新成员 :骨保护蛋白 (ＯＰＧ)、破骨细胞分化因子 (ＲＡＮＫＬ)及其受体 (ＲＡＮＫ)相继被发现 ,它们在人工关节置换术后无菌松动中的作用成为人工关节研究的新热点[1] 。本研究拟建立界膜多核巨细胞分离培养法 ,并初步探讨ＲＡＮＫ在多核巨细胞上的表达。1.资料和方法 :(1)界膜多核巨细胞分离培养 :人工髋关节置换术后无菌松动病人的界膜经手术翻修取得。新鲜界膜…     

界膜

1983年Goldring等发现了松动人工关节与骨之间有一层滑膜样组织,该滑膜样组织能产生大量被称为骨吸收因子的前列腺2（PGE2）和胶原酶。此后越来越多的研究表明界膜是在人工关节中骨-骨水泥或骨-假体界面,特别是在骨溶解部位存在的一层滑膜样纤维结缔组织。松动假体周围的结缔组织膜具有异物肉芽肿的特征并含有假体磨损颗粒。     

人工全髋聚乙烯假体磨损及其生物学效应

目的 探讨人工关节聚乙烯磨损与假体松动的关系。方法 采用光镜与电镜对15例人工髋关节翻修病例的聚乙烯假体臼杯内表面及假体周围软组织作形态学观察。进而在动物实验中观察微小聚乙烯磨损颗粒促使骨吸收性细胞因子增加，植入物周围骨溶解以及植入物-骨整合强度下降的生物效应。结果 聚乙烯假体在人工关节松动形成时均明显磨损，聚乙烯磨损颗粒诱发机体单核-巨噬细胞增殖并分泌骨吸收性细胞因子。结论 聚乙烯磨损与假体松动密度相关。其中生物因素是引起假体松动的主要途径。     

人工关节松动病因的研究

目的：探讨人工关节松动的病因。方法：选择７例松动人工髋关节，翻修手术时取松动关节周围的界膜组织；同时选择１０例骨折内固定患者，拆除内固定物时取内固定物周围瘢痕组织。标本做组织学检查和肿瘤坏死因子（ＴＮＦ）测定。选择１０只成年兔，将２０只模拟假体分别置入双侧股骨远端。分别于术后第６、８、１０、１２、１４周向右侧膝关节腔注射聚乙烯微粒悬液，作为实验侧；左侧膝关节腔注射生理盐水，作为对照侧。第１６周取股骨远端标本，做组织学检查。结果：松动人工髋关节周围的界膜组织主要含大量的组织细胞和聚乙烯微粒，而骨折内固定物周围的瘢痕组织主要为纤维成分，无聚乙烯微粒。松动关节周围界膜组织中的ＴＮＦ浓度明显高于骨折内固定物周围的瘢痕组织（Ｐ＜０．０１）。动物实验发现，实验侧模拟假体周围有一层充满组织细胞的纤维结缔组织界膜，并有明显骨吸收和骨溶解现象，而对照侧无明显纤维结缔组织界膜，也无骨破坏现象。结论：人工关节磨损后，产生大量的磨损微粒，微粒刺激组织细胞分泌ＴＮＦ等溶骨性因子，这些溶骨性因子直接或间接地激活破骨细胞，从而引起假体周围骨吸收、骨溶解，最终导致假体松动。假体松动后又可加重磨损，产生更多的微粒，形成恶性循环     

松动人工髋关节界膜的研究

目的：确定松动人工关节界膜的组织学、超微结构及免疫组化特性，分析假体磨屑对界膜生物学特性的影响。方法：将８例在松动人工关节翻修术中获取的股骨假体－骨间界膜进行光镜、偏振光显微镜、电镜及免疫组化观察。结果：致密纤维结缔组织中有弥温的巨噬细胞及异物巨细胞浸润，纤维母细胞增生，少量淋巴细胞润浸。界膜中和异物巨细胞及巨噬细胞内有大量聚乙烯、骨水泥、金属磨屑。界膜中有大量抗白介素－１β（ＩＬ－１β）抗体染色     

骨保护素和骨保护素配体在假体周围骨溶解中作用的实验研究

目的通过动物实验模拟聚乙烯颗粒诱导假体周围骨溶解,观察骨溶解的组织学反应和界膜内肿瘤坏死因子-α(TNF-α)、骨保护素(OPG)和骨保护素配体(OPGL)的变化,了解上述物质在磨损颗粒诱导假体周围骨溶解中的作用机理。方法实验选用SPF级雄性SD大鼠24只,经双侧膝关节向股骨远端植入钛合金棒,术后2、4、6、8、10周分别向左侧膝关节注入聚乙烯颗粒,右侧注射生理盐水作为对照,术后12周处死动物取材,观察界膜的组织学改变、TNF-α的浓度和OPG、OPGL的mRNA含量变化。所得数据选用配剥t检验进行统计学分析。结果注射颗粒侧钛合金棒周围有明显界膜形成,界膜中的TNF-α也有明显增高。RT-PCR半定量分析发现,注射颗粒侧界膜组织中OPG mRNA水平低于对照侧,而OPGL mRNA水平则高于对照侧(P＜0．05)。结论聚乙烯颗粒可引起钛合金棒周围多种细胞参与的异物肉芽肿反应,成骨细胞/骨髓基质细胞OPGL的合成增加而OPG的合成减少,此过程可能与TNF-α的升高有关。     

钴铬颗粒刺激制备小鼠膝关节假体无菌性松动模型的研究

目的探讨钴铬颗粒刺激制备小鼠膝关节假体无菌性松动模型的可行性。方法取8周龄雄性SCID小鼠24只随机分为实验组及对照组(n=12),于右后肢膝关节胫骨近端髓腔植入钛钉,以模拟人工关节假体置换;其中实验组植入钛钉前于髓腔内注入钴铬颗粒悬液。术后观察小鼠存活情况;术后即刻、2 d及5周时行影像学检查(X线片、CT及Micro-CT骨扫描),观察钛钉位置及胫骨近端骨密度;5周时行生物力学测试以及组织学染色,观察胫骨周围骨组织溶解程度。结果术后实验组2只小鼠死亡,其余小鼠均存活至实验完成。术后影像学检查示对照组钛钉无明显移位,钛钉周围有新生骨痂;实验组钛钉周围存在明显骨溶解。术后5周实验组小鼠右胫骨近端骨密度值为91.25%±0.67%、钛钉-骨界面最大剪切力为(5.93±0.85)N,明显低于对照组的102.07%±1.87%、(16.76±3.09)N,差异均有统计学意义(t=5.462,P=0.041;t=3.760,P=0.046)。组织学观察示实验组钛钉周围可见大量炎症细胞浸润,对照组无明显炎症细胞且有明显骨组织生成。结论采用钴铬颗粒刺激能成功制备小鼠膝关节假体无菌性松动模型。     

阿仑膦酸钠预防磨损颗粒诱导假体周围骨溶解的作用机制

目的 目的是利用阿仑膦酸钠来研究其对人工关节假体周围骨溶解的影响及其作用机制。方法 体重300～350g的雄性SD大鼠24只，经膝关节将特制的钛合金假体及混合磨损颗粒植入胫骨近端（双侧），随机分为实验组和对照组，每组12只，术后分别每日空腹阿仑膦酸钠（0.1mg／kg体重）灌胃和生理盐水2ml灌胃，共6周。术后12周处死取材，进行组织学观察及组织形态计量学测定，并采用ELISA法及半定量RT—PCR检测假体周围组织中TNF-α的的含量及OPGL／OPG含量的比率。结果 组织学观察发现，对照组假体柄周围纤维界膜厚、细胞成分多。可分3层：紧贴假体处为疏松结缔组织，稍外为致密纤维结缔组织。最外层含有单核细胞、巨噬细胞及异物巨细胞。与纤维界膜连接处新生骨边缘呈虫蚀状，新生骨与假体接触少。对假体的支撑作用差。实验组假体周围纤维界膜较薄、细胞成分少，多为成纤维细胞。新生骨与假体间呈点状接触。对假体有明显的支撑作用。形态计量学检测发现，两组间假体周围界膜厚度及面积差异有统计学意义；ELISA和半定量RT—PCR检测假体周围组织中TNF-α及OPGL／OPG发现。两组间差异有统计学意义。结论 阿仑膦酸钠不仅可直接作用于假体周围组织的中破骨细胞。同时可通过调节假体周围组织分泌TNF-α、OPGL、OPG等的含量来调节破骨细胞的分化、成熟及增殖。     

磨损颗粒诱导假体周围骨溶解生物学机制的研究

人工关节置换术是治疗各种晚期关节疾病的有效方法,术后发生人工关节无菌性松动是目前面临人工关节翻修主要原因.人工关节远期松动最常见的原因是假体磨损产生的颗粒诱发假体周围组织细胞产生一系列生物学反应,并导致假体周围骨溶解.大量研究表明,磨损颗粒刺激假体周围的巨噬细胞、成骨细胞、成纤维细胞等产生多种细胞因子,形成破骨细胞性骨吸收,同时影响成骨细胞的分化及功能,抑制骨形成.     

The significance of wear and material fatigue in loosening of hip prostheses

Particles created by wear and disintegration of implant materials give rise to foreign body reactions in the tissue surrounding joint endoprostheses. Histiocytes and foreign body giant cells phagocytize the particles released and form granulomas, which lead in turn to remodelling and resorption of the bone at the interface between implant and bone. As a consequence of this, osteolysis develops, which may lead to loosening and complete failure of fixation of the implant. Radiographically, the areas of osteolysis appear as localized, round, oval or oblong scalloping defects or as radiolucent lines in the endosteal sections of the bone immediately adjacent to the implants. This paper reports on 21 hip joint endoprostheses in which polyethylene and bone cement particles induced large areas of osteolysis at the bone/cement interface. In 8 cases the polyethylene particles originated from the convex joint surfaces of ball heads in "soft-top" endoprostheses (with or without simultaneous replacement of the acetabulum by a metal cup), and in 5 cases they originated from the anchoring surfaces of non-cemented cone-shaped screw-in sockets (Endler type); osteolysis and loosening of these endoprostheses appeared on average 48.2 and 76.6 months after implantation, respectively. The bone cement fragments came from the bone cement mantle of the femur, which had become fractured, disrupted and crushed, in 8 cases of total hip replacement with cemented prostheses; osteolysis appeared on average 87 months after primary implantation in these cases. Tissue samples taken at revision surgery from the joint capsule, the bone/cement interface and the osteolytic areas were processed into histological sections for microscopy and examined in the usual way. The type and amount of phagocytized material were subjected to semiquantitative analysis. We were able to show that osteolysis at the bone/cement interface can be induced by foreign body reactions to abraded polyethylene particles alone as well as by reactions to fragmented bone cement. The morphology of the tissue reaction to particles of the different materials is quite similar. The effect of the foreign body granulomas depends less on the type of the polymer than on the amount of abrasion and fragmentation products released into the surrounding tissue. This again proves that the life-time of joint endoprostheses depends essentially on factors influencing the wear rate. Polymer materials, with low wear resistance, are unsuitable for convex joint surfaces and for direct fixation to bone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhibition of particulate debris-induced osteolysis by alendronate in a rat model.

A rat model was used to study the efficacy of alendronate therapy in inhibition of particle-induced periprosthetic osteolysis. A prosthesis was simulated by inserting a cylindrical polymethylmethacrylate plug into the distal femur of 24 rats allowing the plug to communicate with the joint space. Intra-articular injections of irregularly-shaped ultra-high molecular weight polyethylene particles of 20-200 pm in diameter were administered at 2-week intervals. The rats were randomized into two groups (n=12 each). Group A rats received twice weekly subcutaneous injections of alendronate sodium while group B rats received injections of saline vehicle only. At 10 weeks all rats were sacrificed. The distal femurs were harvested and axial sections were prepared for histologic analysis. Each section was graded on a scale of 1-4, quantifying the degree of osteolysis surrounding the polymethylmethacrylate plug. Microscopic examination showed a significant (P<.0001) difference in the amount of periprosthetic bone. Femurs from group A treated with alendronate demonstrated mostly normal or near-normal periprosthetic trabeculations, whereas femurs from group B treated with saline showed extensive bone resorption. There was no qualitative difference in the inflammatory cellular response between the groups. This study established the ability of alendronate to inhibit the osteoclastic-mediated osteolysis around joint implants.     

A rat model of resorption of bone at the cement-bone interface in the presence of polyethylene wear particles

Resorption of bone and the formation of a membrane at the interface between acrylic cement and bone were induced by particles of high-density polyethylene that were similar in size to those that are present in the tissues surrounding a human joint prosthesis. A non-weight-bearing plug of methylmethacrylate was inserted through the knee joint into the distal part of the femur of the rat. The plug rapidly became surrounded by a shell of bone. After repeated injections of particles of high-density polyethylene into the knee joint, resorption of bone occurred at this stable interface. No resorption of bone occurred after the opposite knee was injected with a control preparation that did not contain particles. The resorption of bone that occurred around the plug after the injection of particles of polyethylene took place in the absence of mechanical causes for loosening and in the absence of infection.     

磨屑在人工关节无菌性松动中作用的实验研究

目的：观察磨屑在动物体内引起的组织学反应，比较了不同磨屑所致反应差别，比较磨屑在羟基磷灰石涂层钛合金棒－骨界面和光滑钛合金棒－骨界面间移动差别，探讨人工关节无菌性松动机制。方法：６４只家兔分为８组（ｎ＝８），分别将羟基磷灰石涂层钛合金棒和光滑钛合金棒经膝关节置入股骨远端，定期膝关节注入聚乙烯，钛合金及两者的混合磨屑。光镜、偏振光显微镜和电镜观察关节滑膜、两种钛合金棒－骨界面的组织学和超微结构。结果     

Tissue response to the failed Gerard double-cup: Histologic analysis of 40 uncemented hip arthroplasties

Femoral head remnants, joint capsules and acetabular membranes were retrieved at revision of 40 failed uncemented, Gerard double-cup hip arthroplasties. All femoral heads were covered with a fibrous membrane containing polyethylene and metal particles, macrophages, and giant cells. The same histopathologic features were found in the joint capsules and acetabular membranes. There was a relationship between the amount of polyethylene particles in the fibrous membrane of the femoral head and the presence of osteonecrosis. Resorption of necrotic bone contributed to failure of the arthroplasty, aided by granulomatous reactions to the wear particles that appeared to induce osteolysis. The overall findings indicate that the severity of the foreign body reaction in periprosthetic tissues is related to the amount of wear particles.

Future designs of resurfacing hip arthroplasties should be focused on wear-resistant material combinations.     

Histological analysis and biological effects of granulation tissue around loosened hip prostheses in the development of osteolysis

Although aseptic loosening of the prosthesis is a long-term complication after total joint replacement, the detailed mechanism of osteolysis remains unknown. We examined 82 samples from 40 patients with aseptic loosened hip prostheses histologically, and compared the distribution of particles, macrophages/histiocytes, and foreign body giant cells in the retrieved tissue from capsules and around prostheses. Furthermore, to investigate the mechanism of osteolysis, we cultured tissue from a patient with massive osteolysis and examined the effects of the conditioned medium on osteoblasts in vitro. Numerous multinucleated giant cells and histiocytes were present, and polyethylene particles ranging from medium to large were identified in the polarized light. However, the distribution was heterogeneous, and no particles were found microscopically in about 30%–40% of periprosthetic tissues, and in 60% of capsules. The amount of particles correlated with giant cells, but not with histiocytes. The conditioned medium of the granulation tissue culture stimulated osteoblasts to produce interleukin-6 in both protein and mRNA, and this was in part inhibited by anti-tumor necrosis factor- or the interleukin-1 antibody, suggesting that interleukin-6 production is mediated by several cytokines. These findings suggest that interleukin-6, which is produced not only by macrophages but also by osteoblasts, is a contributing factor to aseptic loosening.     

Osteolysis in alloarthroplasty of the hip. The role of bone cement fragmentation

Movement at the interface between bone and cement and fractures of the cement can cause fragmentation of the polymethylmethacrylate (PMMA) bone cement implant. In order to obtain further information about the effect of PMMA fragments on the surrounding tissue and the role of such particles in the development of bone resorption, the authors investigated 17 patients with cemented total hip endoprostheses showing osteolysis and implant loosening in the femoral shaft with (Group B) and without (Group A) involvement of the acetabulum. The roentgenographic follow-up examinations revealed an initially slow and later more rapid extension of the endosteal bone erosions, with a predilection for the tip of the stem, the lesser trochanter, and laterally for the middle of the stem. At revision surgery, tissue samples were taken from the joint capsule and the bone-cement interface, in particular from the osteolysis in the femoral shaft and the acetabulum. The tissue samples were processed for histology, microscopically examined, and semiquantitatively evaluated. The retrieved devices were also carefully inspected. Large foreign-body granulomas were found at the bone-cement interface and in the joint capsule. Histiocytes and foreign-body giant cells stored particles of PMMA and polyethylene, of which fragmented bone cement predominated. Granulomatous tissue invaded bone canals and marrow spaces and induced resorption of the surrounding bone. In four cases in Group A, tissue from the osteolysis contained only fragmented bone cement, demonstrating that PMMA particles alone may be responsible for triggering focal bone resorption. Osteolysis seems to begin at the site where disintegration of bone cement begins. In cases in which polyethylene particles were found in the tissue in addition to fragmented bone cement, wear from the ultrahigh molecular weight polyethylene socket has been increased by entrapment of PMMA particles between the joint surfaces. Thus, fragmentation of bone cement and abrasion of polyethylene enhance each other. Bone cement particles promote polyethylene wear, which in turn promotes granuloma formation, bone resorption, and subsequent bone cement disintegration.     

Role of free radicals in aseptic loosening of hip arthroplasty.

Fibrous pseudocapsule around hip implants is an invariable finding at revision operations and is believed to release inflammatory mediators that stimulate bone resorption. Reactive oxygen species have been proposed to be causative factors in various disorders with tissue fibrosis. We were interested in investigating whether aseptic loosening is connected with high oxidative stress, and in showing the underlying mechanism of periprosthetic fibrosis and its role in loosening. Levels of oxidative stress markers reduced (GSH) and oxidized (GSSG) gluthatione and malondialdehyde (MDA) were assayed in 28 loose hips and in 12 stable hips revised for high rate of wear and osteolysis. Collagen in the periprosthetic tissues was measured as hydroxyproline content. Osteolysis and polyethylene wear were graded. Increased oxidative stress measured by low GSH/GSSG ratio as well as by increased MDA level was established in patients compared to controls. Oxidative stress markers intercorrelated significantly. MDA and both GSH and GSSG levels correlated significantly with hydroxyproline level. Levels of GSSG and MDA were higher in hips with greater polyethylene wear. The results suggest that high oxidative stress may play a role in formation of a fibrous membrane observed at revision of loose hips. The fibrous pseudocapsule is probably related to high intraarticular pressure and expansion of the effective joint space. This study may elicit some aspects of the pathogenesis of aseptic hip loosening and aid in future investigations aiming at prevention of this complication.     

阿仑膦酸钠对假体周围骨溶解中OPG及RANKL的影响

目的 探讨阿仑膦酸钠对聚乙烯颗粒诱导假体周围骨溶解中OPG及RANKL影响.方法 将钛金属棒植入新西兰大白兔左侧股骨内,每2周向左膝关节内注射聚乙烯颗粒,使用随机数字表随机分成实验组和对照组,各6只.实验组给予阿仑膦酸钠灌胃,而对照组给予等量的0.9％的氯化钠溶液灌胃.12周后处死动物,取出假体周围界膜组织,用ELIS...