本文選題：鎂 + 穿心蓮內(nèi)酯��； 參考：《上海交通大學(xué)》2015年博士論文

【摘要】：背景和目的無菌性松動是人工關(guān)節(jié)置換遠期失效的主要原因,而磨損顆粒誘導(dǎo)的假體周圍骨溶解則是造成無菌性松動的罪魁禍首。這一過程的發(fā)生與以下三個因素密切相關(guān):炎性因子浸潤、骨吸收亢進及骨生成障礙。三者相互促進,我們對任何一方的輕視,都將在無菌性松動的防治中付出代價。與此同時,感染也是關(guān)節(jié)置換的主要并發(fā)癥之一,其結(jié)果具有災(zāi)難性,假體常需取出,并行二次翻修術(shù)。研究表明,內(nèi)植物表面細菌黏附和生物膜的形成是假體感染形成的關(guān)鍵環(huán)節(jié)。而矛盾的是,骨內(nèi)植物需滿足良好的生物相容性,促進成骨細胞黏附以利于骨整合,但這無疑又會促進細菌黏附進而增加感染的機會。因此,理想的骨內(nèi)植物材料需兼顧促進骨整合和抗感染活性。本課題擬針對磨損顆粒誘導(dǎo)骨溶解的發(fā)生機制,從對抗炎癥因子釋放、抑制骨吸收及促進骨形成的角度出發(fā),探討鎂降解產(chǎn)生的局部微環(huán)境在防治假體無菌性松動中的潛在應(yīng)用價值。并觀察鎂作為骨內(nèi)植物的抗感染性能。同時,從調(diào)控機體全身骨代謝為出發(fā)點,探討植物天然提取物穿心蓮內(nèi)酯(Andrographolide)的全身骨保護作用。以期從局部及全身出發(fā),對抗磨損顆粒誘導(dǎo)骨溶解的發(fā)生,為防治假體無菌性松動提供新手段。內(nèi)容與方法1.按照國標ISO10993浸泡鎂(99.9%)模擬鎂降解產(chǎn)物(Magnesium Degradation,Mg D),觀察鎂降解產(chǎn)物對單核-巨噬細胞(BMMS)增殖、破骨細胞分化及骨吸收功能的影響,探討其引起的破骨細胞應(yīng)答反應(yīng);建立磨損顆粒誘導(dǎo)小鼠顱骨溶解模型,利用micro-CT、組織形態(tài)計量等評價鎂降解產(chǎn)物對骨溶解的抑制效果。觀察鎂降解產(chǎn)物對骨髓間充質(zhì)干細胞(BMSC)粘附、鋪展、增殖及向成骨細胞分化的影響,探討其引起的h BMSC應(yīng)答反應(yīng)。2.體外觀察鎂(99.9%)的抗耐甲氧西林金黃色葡萄球菌(MRSA)效果,建立SD大鼠骨髓炎模型,將鎂棒作為髓內(nèi)釘放入大鼠髓腔內(nèi),觀察對骨髓炎的治療效果和周圍骨量的改變,并探討作用機制。3.通過觀察Andrographolide對成骨細胞和破骨細胞分化及功能的影響,探討其引起的骨應(yīng)答反應(yīng),并闡述其作用機制;建立磨損顆粒誘導(dǎo)局部骨溶解模型和LPS誘導(dǎo)全身炎癥性骨丟失模型,腹腔注射Andrographolide,利用micro-CT、組織形態(tài)計量等評價Andrographolide對小鼠局部和全身的骨保護作用。結(jié)果1.鎂降解產(chǎn)物通過抑制破骨細胞特異性轉(zhuǎn)錄因子NFATc1的轉(zhuǎn)錄活性,進而顯著抑制破骨細胞形成和骨吸收功能;在磨損顆粒誘導(dǎo)骨溶解小鼠體內(nèi),鎂降解產(chǎn)物降低組織中活化破骨細胞數(shù)量和炎癥因子TNF-?、IL-1β及RANKL水平,顯著抑制骨丟失。此外,鎂降解產(chǎn)物提高BMSC表面integrinα3/α5/β1表達水平,促進BMP2下游SMADs復(fù)合物核轉(zhuǎn)位,增強BMSC增殖、黏附及成骨分化功能,但并不利于胞外鈣沉積。2.鎂在體外顯著抑制MRSA的粘附和生物膜的形成,這可能得益于鎂降解產(chǎn)生的堿性環(huán)境。同時,鎂植入骨髓腔后顯著抑制骨髓炎的進展,并有大量新生骨。3.體外研究發(fā)現(xiàn),Andrographolide通過抑制RANKL下游p65入核和ERK磷酸化,進而發(fā)揮抑制破骨細胞功能的作用。與此同時,Andrographolide提高成骨標志性基因的表達和OPG/RANKL水平,促進成骨分化,促進骨代謝向骨生成方向發(fā)展。在LPS誘導(dǎo)的全身性骨丟失和磨損顆粒誘導(dǎo)局部骨溶解中,Andrographolide顯著改善炎癥浸潤和骨溶解,骨小梁表面破骨細胞數(shù)量顯著減少,顯示出良好的骨保護作用。結(jié)論1.鎂降解產(chǎn)生的微環(huán)境可抑制破骨細胞分化和骨吸收功能,促進BMSC增殖、粘附和成骨分化,降低炎癥因子水平,對抗骨溶解發(fā)生機制,抑制磨損顆粒誘導(dǎo)的局部骨丟失。鎂可能成為未來防治骨溶解疾病的新手段。2.鎂在體外抑制MRSA粘附和生物膜形成,在體內(nèi)抑制骨髓炎進展并減少感染周圍骨丟失。3.Andrographolide抑制破骨細胞分化和骨吸收,促進成骨分化,在全身水平降低炎癥水平,正向調(diào)節(jié)骨代謝,具有顯著的全身骨保護作用。
[Abstract]:Background and objective: aseptic loosening is the main reason for the failure of artificial joint replacement in the long term, and the wear particle induced periprosthesis osteolysis is caused by arch-criminal aseptic loosening. This process is closely related to the following three factors: the infiltration of inflammatory factors, bone resorption and bone formation obstacles. Hyperthyroidism three promote each other we despise, to any party, will pay the price in the prevention and treatment of aseptic loosening. At the same time, one of the major complications of infection and joint replacement, the results are disastrous, often need to remove the prosthesis two times, parallel revision. The study shows that the formation of plant surface bacterial adhesion and biofilm is the key link of periprosthetic infection formation. Paradoxically, bone implants required good biocompatibility, promote osteoblast adhesion to bone integration, but this will undoubtedly promote the adhesion of bacteria and Increase the chance of infection. Therefore, the ideal bone implant materials should be taken into consideration to promote osseointegration and anti infection activity. This paper according to the mechanism of wear debris induced osteolysis, released from against inflammatory factors, inhibit bone resorption and promote bone formation in the perspective of local magnesium produced by the degradation of micro environment in aseptic loosening the prevention of prosthesis in potential applications. And to observe the bone magnesium as plant anti infective properties. At the same time, from the regulation of bone metabolism as a starting point to explore the natural plant extract andrographolide (Andrographolide) of the bone protective effect. In order from the perspective of local and systemic confrontation, wear particles induced osteolysis, provide a new method for prevention and treatment of aseptic loosening of the prosthesis. The contents and methods in accordance with the national standard ISO10993 1. for magnesium (99.9%) magnesium degradation products (Magnesium Degradation simulation, Mg, D) on magnesium reduction The hydrolysate on mononuclear macrophage (BMMS) proliferation, osteoclast differentiation and bone resorption of osteoclasts, which caused the response; establish mice induced by skull dissolution model, wear particles by micro-CT, the inhibitory effect of histomorphometric evaluation of magnesium degradation products on osteolysis. Observe the degradation products of magnesium bone marrow mesenchymal stem cells (BMSC) adhesion, spreading, proliferation and osteogenic differentiation in vitro, observe the magnesium in vitro h BMSC response induced by the.2. (99.9%) of methicillin resistant Staphylococcus aureus (MRSA) effect, establish the SD rat model of osteomyelitis, the magnesium stick as intramedullary nail into the medullary cavity of rats, to observe the therapeutic effect and osteomyelitis of the bone mass around the change, and to investigate the mechanism of.3. by observing the effect of Andrographolide on osteoblast and osteoclast differentiation and function, to explore its causes The bone response, and discuss the mechanism; establish local model and LPS induced osteolysis induced systemic inflammatory bone loss model of wear particles, intraperitoneal injection of Andrographolide, using micro-CT, bone histomorphometry and evaluate the protective effect of Andrographolide on local and systemic mice. Results 1. mg degradation products by inhibiting transcriptional activity of osteoclast specific the transcription factor NFATc1, and inhibit osteoclast formation and bone resorption in vivo; wear particles induced osteolysis, osteoclast number and inflammatory factor TNF- activation of magnesium degradation products reduce the organization?, IL-1 beta and RANKL level, inhibit bone loss. In addition, the degradation products of magnesium increased BMSC surface integrin alpha 3/ alpha 5/ beta 1 expression, promote BMP2 downstream SMADs complex nuclear translocation, enhanced BMSC proliferation, adhesion and osteogenic differentiation and function, but unfavorable to extracellular calcium deposition. The formation of 2. mg in vitro significantly inhibited MRSA adhesion and biofilm alkaline environment, this may be due to the degradation of magnesium production. At the same time, the progress of magnesium implanted bone marrow cavity significantly inhibited osteomyelitis, and a large amount of new bone.3. in vitro, Andrographolide through inhibition of RANKL downstream nuclear translocation of p65 and ERK phosphorylation, and play the inhibition of osteoclast function. At the same time, improve the Andrographolide of osteoblast marker gene expression and OPG/RANKL levels, and promote osteogenic differentiation, promote bone metabolism to bone formation and lose direction. The wear particle induced osteolysis in local systemic bone induced by LPS, Andrographolide significantly improved the inflammatory infiltration and bone osteolysis on the surface of the number of osteoclasts were significantly decreased, bone showed good protective effect. The micro environment of the conclusion of the 1. mg degradation can inhibit osteoclast differentiation and bone resorption, To promote BMSC proliferation, adhesion and osteogenic differentiation, decrease the level of inflammatory factors and mechanism against osteolysis, wear particle induced inhibition of local bone loss. Magnesium may become the new direction of prevention and treatment of diseases of.2. magnesium osteolysis inhibited MRSA adhesion and biofilm formation in vitro, inhibition of osteomyelitis progress and reduce infection inhibit the differentiation and bone loss around.3.Andrographolide bone resorption in osteoclasts in vivo, promote osteogenic differentiation, reduce the level of inflammation at the systemic level, positive regulation of bone metabolism, bone has a significant protective effect.

【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R687.4

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