本文關(guān)鍵詞： 人工關(guān)節(jié) 無菌性松動 骨溶解 動物模型 二膦酸鹽 涂層　出處：《第四軍醫(yī)大學》2009年碩士論文　論文類型：學位論文

【摘要】： 關(guān)節(jié)置換手術(shù)隨著人群的老齡化逐漸增加。隨之而來就出現(xiàn)了一個大問題,即越來越多的患者需要進行至少一次的返修手術(shù)。翻修的首要原因除了感染就是假體無菌性松動。以UHMWPE顆粒為主,引起的假體周圍骨溶解是無菌性松動的首要原因。許多研究已經(jīng)指出非骨水泥假體的壽命很大程度上取決于生物學固定效果。假體的早期移動會增加假體無菌性松動的危險。因此假體的初始穩(wěn)定性至關(guān)重要,迅速而持續(xù)的骨長入可以為假體提供良好的生物學固定,預防假體移動。同時,假體周圍新生骨組織的密度越高,骨-假體界面抵抗磨屑顆粒引起的骨溶解作用越強。 HA涂層可以增強假體的穩(wěn)定性、骨-假體界面的結(jié)合強度和抗疲勞性能、骨礦化水平和骨長入速率。同時二膦酸鹽類藥物可以改善假體的生物學固定效果。最近很多實驗關(guān)注將二膦酸鹽與假體結(jié)合,結(jié)果表明二膦酸鹽復合涂層可以刺激假體周圍新骨的形成和力學性能的改善。目前需要研究的問題是: 1.缺少一種既符合人工關(guān)節(jié)假體無菌性松動病理特點又簡便有效的動物模型。 2.阿侖膦酸鈉復合HA涂層的非多孔鈦假體是否可以抑制UHMWPE顆粒誘導的假體周圍骨溶解。 3.阿侖膦酸鈉在預防磨屑誘導的假體周圍骨溶解過程中是否能夠影響成骨細胞的活性。 4.阿侖膦酸鈉的局部釋放是否具有于系統(tǒng)性治療效果。 5.阿侖膦酸鈉復合HA涂層假體是否能夠作為一種緩釋載體為假體固定提供支持。 因此,本實驗通過UHMWPE顆粒誘導建立了新西蘭大白兔的人工關(guān)節(jié)無菌性松動動物模型。同時在此模型基礎(chǔ)上,通過病理學、影像學、骨組織形態(tài)學、生物力學等方面的觀測,進一步研究以上問題。具體內(nèi)容如下: 1.X線測量 動物處死后即刻拍攝雙側(cè)脛骨正側(cè)位X線,觀察左側(cè)脛骨假體周圍骨溶解的影像學改變,并測量雙側(cè)脛骨髓腔峽部骨皮質(zhì)厚度。 2.病理學檢測 膝關(guān)節(jié)滑膜HE染色,分別用普通光鏡和偏振光鏡觀察滑膜結(jié)構(gòu),包括是否增生肥厚、是否有炎細胞浸潤以及UHMWPE顆粒是否被滑膜組織包繞吞噬等。 3.生物力學測量 通過假體拔出實驗(pull-out test)描繪負荷-位移曲線,采集好負荷-位移曲線后計算極限抗剪強度、表觀抗剪強度和總能量吸收值。 4.骨組織形態(tài)學測量 進行四環(huán)素熒光雙標記,分別通過熒光切片和甲苯胺藍染色切片來計算骨組織形態(tài)學動態(tài)和靜態(tài)指標。依照ASBMR命名法來計算以下參數(shù):骨密度(BV/TV)、骨小梁厚度(Tb.Th)、骨小梁數(shù)量(Tb.N)、類骨質(zhì)表面(OS/BS)、類骨質(zhì)厚度(O.Th)以及骨形成速率(BFR/BS)、松質(zhì)骨骨礦沉積率(MAR)和皮質(zhì)骨骨礦沉積率(E-MAR)。 通過改良麗春紅三色切片來計算骨-假體接觸率和骨體積分數(shù)兩項指標。 通過VON KOSSA染色切片來計算骨皮質(zhì)處鈣鹽沉積島平均面積、鈣鹽沉積島數(shù)量和鈣鹽沉積島面積分數(shù)(鈣鹽沉積島總面積/骨組織面積)。 5.掃描電鏡測量 分別在普通模式和背散射模式下觀測。左側(cè)脛骨標本分別測量距離假體表面200μm、200-500μm和500-800μm處的骨體積分數(shù),以及距離骨內(nèi)膜表面800μm處的骨體積分數(shù),右側(cè)測量距離骨內(nèi)膜表面800μm處的骨體積分數(shù)并于普通模式下觀測標本表面顯微形態(tài)。 6.Ash Weight 測定右側(cè)尺骨在灼燒前后的重量,標本稱濕重(Ww),然后于密閉坩堝內(nèi)480℃燒24h,稱干重(Wa),計算干濕比(Wa/Ww),以此反映標本內(nèi)鈣鹽含量。 7.DEXA 測量第2腰椎骨密度值。 8.阿侖膦酸鈉體外釋放周期 繪制阿侖膦酸鈉體外釋放曲線,用來評估此新型復合涂層假體的藥物緩釋能力。 以上檢測結(jié)果均顯示阿侖膦酸鈉的局部應用可以增加術(shù)側(cè)和對側(cè)的骨皮質(zhì)厚度,骨小梁參數(shù),成骨細胞活性,骨礦化水平和骨密度,并能顯著增加術(shù)側(cè)骨皮質(zhì)厚度,假體生物力學固定強度,骨-假體接觸率,假體周圍骨體積分數(shù),骨礦化水平和假體周圍骨密度。 結(jié)論: 1.我們建立的新西蘭大白兔人工關(guān)節(jié)無菌性松動動物模型無論從病理機制還是造模效果上都能為研究相關(guān)課題提供基礎(chǔ),并且造模簡便可靠。 2.在體內(nèi),阿侖膦酸鈉復合HA涂層的非多孔鈦假體可以明顯抑制UHMWPE顆粒誘導的假體周圍骨溶解,甚至比在沒有磨屑顆粒的情況下單獨使用HA涂層假體取得的效果都要好。 3.在體內(nèi),阿侖膦酸鈉在預防磨屑誘導的假體周圍骨溶解過程中能夠促進成骨細胞的活性。 4.阿侖膦酸鈉的局部釋放具有于系統(tǒng)性治療效果。 5.阿侖膦酸鈉復合HA涂層作為一種緩釋載體,一方面能夠為假體的初始穩(wěn)定性提供早期短時間的高藥物濃度釋放,另一方面又能夠提供長時間的低濃度藥物緩釋。
[Abstract]:Joint replacement surgery increased gradually with the aging of the population. It will be a big problem that more and more patients need surgical repair. At least one of the leading causes of revision surgery in addition to infection is aseptic loosening. The UHMWPE particles mainly caused by periprosthetic osteolysis is the primary cause of aseptic loosening. Many studies have pointed out that the life of non bone cement prosthesis depends largely on the biological fixation. Early mobile prosthesis would increase the risk of aseptic loosening of the prosthesis. The prosthesis initial stability is crucial, rapid and sustained bone ingrowth canprovide good biological fixation, prevention of prosthesis movement. At the same time, around the prosthesis of newborn the higher the density of bone tissue, bone prosthesis interface resistance effect of wear debris induced osteolysis is stronger.
HA coating can enhance the stability of the prosthesis, bone prosthesis interface bonding strength and anti fatigue performance, bone mineralization and bone ingrowth rate. The effect of biological fixation and bisphosphonates can improve the prosthesis. Recently a lot of experiments concerning bisphosphonates and prosthesis combined with, results show that the composite coating can stimulate the formation of bisphosphonates and mechanical properties around the prosthesis the new bone improvement. The current need to study the problem is:
1. there is a lack of an animal model which is not only in accordance with the pathological characteristics of aseptic loosening of artificial joint prosthesis, but also simple and effective.
Whether the non porous titanium prosthesis 2. alendronate HA composite coating can inhibit UHMWPE particles induced osteolysis.
3. of alendronate sodium in the prevention of grinding affect the activity of osteoblasts to periprosthetic osteolysis induced by process chip.
Whether the local release of 4. alendronate has a systemic therapeutic effect.
5. alendronate compound HA coated prosthesis can provide support for prosthesis fixation as a kind of sustained-release carrier.
Therefore, this experiment established by the artificial joint aseptic loosening animal model in New Zealand rabbits by UHMWPE particles. Based on this model, the pathology, imaging, histological observation, biomechanical aspects of the further research on the above problems. The specific contents are as follows:
1. X ray measurement
The animal were sacrificed immediately after the shooting of bilateral tibial lateral X ray imaging observation, left tibial periprosthetic osteolysis pathology, and measurement of bilateral tibial bone marrow cavity isthmus thickness of cortical bone.
2. pathological examination
The synovial membrane of knee joint was stained with HE. The synovial membrane structure was observed by ordinary light microscope and polarized light microscope, including whether hypertrophy, inflammatory cell infiltration and UHMWPE particles were surrounded by synovial tissue.
3. biomechanical measurement
The load displacement curve is depicted through the prosthesis pull out test (pull-out test), and the ultimate shear strength, apparent shear strength and total energy absorption value are calculated after the load displacement curve is collected.
4. morphologic measurement of bone histomorphology
For tetracycline double labeling respectively to calculate the bone morphology index and the static and dynamic slicing through fluorescence sectioning and toluidine blue staining. According to ASBMR nomenclature to calculate the following parameters: bone mineral density (BV/TV), Liang Houdu (Tb.Th), trabecular bone trabecular bone volume (Tb.N), osteoid surface (OS/BS), osteoid thickness (O.Th) and bone formation rate (BFR/BS), cancellous bone mineral deposition rate (MAR) and cortical bone mineral deposition rate (E-MAR).
Two indexes of bone prosthesis contact rate and bone volume fraction were calculated by improving the tricolor slice of Li Chun Hong.
VON KOSSA staining slices were used to calculate the average area of calcium salt deposition Island, the number of calcium deposition islands and the area of calcium deposition island area (the total area of calcium deposition Island / bone tissue area).
5. scanning electron microscopy
Were observed in the normal mode and the back scattering mode. The left tibia specimens were measured from the surface of the artificial bone volume fraction 200 m, 200-500 m and 500-800 m, and the distance between the endosteal surface 800 m bone volume fraction, bone volume fraction on the right side of the measurement distance the endosteal surface of 800 m. Observation of surface morphology and specimens in normal mode.
6.Ash Weight
The weight of the right ulna is measured before and after burning. The specimen is called wet weight (Ww), then 24h is burned at 480 degree C in the closed crucible, and the dry weight (Wa) is calculated. The dry wet ratio (Wa/Ww) is calculated to reflect the calcium content in the specimen.
7.DEXA
The BMD of the second lumbar vertebrae was measured.
In vitro release cycle of 8. alendronate
The release curve of alendronate in vitro was designed to evaluate the drug release ability of the new composite coating prosthesis.
The results above showed that local application of alendronate can increase the operative side and contralateral cortical bone thickness, trabecular bone parameters, the activity of osteoblasts, bone mineralization and bone density, and can significantly increase the operative side of cortical bone thickness, the fixation strength of prosthesis biomechanics, bone implant contact, prosthesis around the bone volume fraction, bone density around the prosthesis and bone mineralization.
Conclusion:
1., the animal models of aseptic loosening of artificial joints in New Zealand white rabbits established by us can provide foundation for research related topics, no matter from pathological mechanism or modeling effect, and the models are simple and reliable.
2. in vivo, non porous titanium implant alendronate HA composite coating can inhibit UHMWPE particles induced osteolysis, even more than in the absence of UHMWPE particles used alone HA coated prosthesis works better.
3. in vivo, alendronate sodium in the prevention of wear debris induced osteolysis process can promote the activity of osteoblasts.
The local release of 4. alendronate has a systemic therapeutic effect.
5. alendronate sodium composite HA coating as a slow release carrier, on the one hand, can provide early, short time high drug concentration release for the initial stability of the prosthesis, and on the other hand, it can provide long time low concentration drug release.

【學位授予單位】：第四軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2009
【分類號】：R-332;R687

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