發(fā)布時間：2018-05-03 22:11

  本文選題：d電子合金設(shè)計 + 放電等離子燒結(jié)　； 參考：《吉林大學(xué)》2016年博士論文

【摘要】：目的:鈦合金的生物相容性優(yōu)良,是目前比較通用的生物醫(yī)用金屬材料。但在應(yīng)用過程中依然存在彈性模量相對較高和植入體與骨組織結(jié)合力的問題。植入體與骨組織彈性模量的差異會造成界面應(yīng)力傳導(dǎo)不良,影響周圍骨組織的再生、改建,降低骨密度和骨強(qiáng)度,引發(fā)骨植入體松動甚至失效。華南理工大學(xué)開發(fā)了一種名義成分為(Ti-35Nb-7Zr-5Ta)98Si2的新型β型鈦合金,該合金采用d電子合金設(shè)計理論設(shè)計,放電等離子燒結(jié)法(SPS)制造,具備低彈性模量(37GPa)、高強(qiáng)度、高塑性以及超細(xì)晶結(jié)構(gòu)。其中,Ti-35Nb-7Zr-5Ta合金體系已經(jīng)被證實具有良好的生物相容性和較低的彈性模量,而硅(Si)元素具有增加非晶形成和晶粒細(xì)化的功能,同時也具有良好的相容性。(Ti-35Nb-7Zr-5Ta)98Si2合金的彈性模量遠(yuǎn)低于Ti-6Al-4V且更接近人骨。本研究旨在通過評價該合金的耐蝕性、生物相容性、生物活性以及骨整合能力,探討其生物安全性及骨科應(yīng)用價值,為其應(yīng)用到臨床提供一定的理論依據(jù)。方法:(1)耐腐蝕性評價:將合金試樣在生理鹽水中浸泡1d、7d、14d、30d、60d,分別比較浸泡過程中生理鹽水的PH值變化、浸泡前后合金試樣的重量變化和掃描電鏡下表面形貌改變,以探究其耐腐蝕性能。(2)生物相容性評價:制備(Ti-35Nb-7Zr-5Ta)98Si2合金浸提培養(yǎng)液,用浸提液培養(yǎng)L-929小鼠成纖維細(xì)胞,在培養(yǎng)1d、2d、3d、5d、7d時通過光鏡觀察細(xì)胞生長狀態(tài)并行MTT法細(xì)胞毒實驗,結(jié)合醫(yī)用材料細(xì)胞毒性評價標(biāo)準(zhǔn)對合金細(xì)胞毒性進(jìn)行分析;受試小鼠腹腔注射受試材料生理鹽水浸提液,觀察小鼠注射后24h、48h、72h的狀態(tài),參照全身毒性反應(yīng)評價標(biāo)準(zhǔn)分析合金的急性全身毒性;將合金試樣直接敷貼于受試實驗動物皮膚或在皮內(nèi)注射合金浸提液,觀察局部反應(yīng),以評價試樣皮膚/皮內(nèi)刺激性;合金試樣植入實驗動物骨內(nèi),3個月后取出試樣及其周圍骨組織,硬組織切片、HE染色,顯微鏡觀察,評價材料植入骨組織后所引起的局部反應(yīng)。(3)生物活性評價:小鼠前成骨細(xì)胞MC3T3-E1與(Ti-35Nb-7Zr-5Ta)98Si2合金試樣共同培養(yǎng),分別于1h、3h、6h進(jìn)行吖啶橙染色,顯微鏡下計數(shù)表面粘附細(xì)胞并與Ti-6Al-4V合金對比,評價新合金對成骨細(xì)胞粘附的影響;對與成骨細(xì)胞共培養(yǎng)24h的(Ti-35Nb-7Zr-5Ta)98Si2合金表面噴金,掃描電鏡下觀察粘附細(xì)胞的形態(tài);Annexin V-FITC法染色成骨細(xì)胞,流式細(xì)胞儀檢測細(xì)胞的凋亡率;ELISA法檢測成骨細(xì)胞白細(xì)胞介素-6/堿性磷酸酶的分泌量,評價細(xì)胞炎性反應(yīng)及(Ti-35Nb-7Zr-5Ta)98Si2合金對成骨細(xì)胞早期分化的影響;MC3T3-E1細(xì)胞與(Ti-35Nb-7Zr-5Ta)98Si2合金共培養(yǎng)30d,茜素紅染色細(xì)胞外基質(zhì)礦化結(jié)節(jié),評價新合金對成骨細(xì)胞晚期分化及細(xì)胞外基質(zhì)礦化的影響。(4)骨整合能力評價:選擇6只健康成年新西蘭大白兔作為受試動物,體重2.5~3kg,每只受試動物雙側(cè)股骨分別植入Ti-6Al-4V和(Ti-35Nb-7Zr-5Ta)98Si2合金,每側(cè)股骨植入3個。術(shù)后3個月處理受試動物。肉眼及X線檢查材料-骨界面及周圍組織的情況;取出帶有植入材料的動物股骨行硬組織切片,并進(jìn)行Masson染色及甲苯胺藍(lán)染色,計算骨結(jié)合率(BCR);進(jìn)行力學(xué)推出實驗,以最大推出力評價植入材料與骨組織的結(jié)合強(qiáng)度。結(jié)果:(1)材料在生理鹽水中浸泡1d、7d、14d、30d、60d,各時間點檢測溶液PH值,未見明顯變化;浸泡后合金試樣的重量沒有明顯減小;通過掃描電鏡比較合金表面浸泡前和浸泡后的形貌,表面光潔度相似,未發(fā)現(xiàn)腐蝕痕跡,結(jié)果表明(Ti-35Nb-7Zr-5Ta)98Si2合金的耐腐蝕性能良好。(2)小鼠成纖維細(xì)胞L-929在合金浸提液中生長狀態(tài)良好,沒有發(fā)現(xiàn)明顯細(xì)胞毒性,細(xì)胞形態(tài)與普通培養(yǎng)基培養(yǎng)的細(xì)胞無差異;MTT檢測結(jié)果證實(Ti-35Nb-7Zr-5Ta)98Si2合金的細(xì)胞毒性在0~Ⅰ級,符合生物安全標(biāo)準(zhǔn);腹腔注射受試材料浸提液的小鼠未出現(xiàn)腹膜刺激癥狀、呼吸抑制、運(yùn)動減少、發(fā)紺、腹瀉、震顫及死亡等反應(yīng),證明新合金不會引起全身毒性;表面敷貼合金試樣和皮內(nèi)注射浸提液的實驗動物未出現(xiàn)局部不良反應(yīng),證實新合金對皮膚及皮內(nèi)無刺激性;骨植入后切片觀察,合金植入體周圍未發(fā)生骨組織的壞死、炎癥等副反應(yīng)。(3)吖啶橙染色結(jié)果表明(Ti-35Nb-7Zr-5Ta)98Si2合金表面粘附細(xì)胞未出現(xiàn)壞死或凋亡,表面粘附細(xì)胞計數(shù)與Ti-6Al-4V合金相近,二者無顯著差異;掃描電鏡觀察材料表面顯示成骨細(xì)胞在新合金表面生長狀態(tài)良好;細(xì)胞凋亡實驗表明(Ti-35Nb-7Zr-5Ta)98Si2合金組的細(xì)胞凋亡率與Ti-6Al-4V及陰性組無明顯差別;成骨細(xì)胞白細(xì)胞介素-6和堿性磷酸酶的分泌量未見明顯增高;成骨細(xì)胞與受試材料共培養(yǎng)30d后,(Ti-35Nb-7Zr-5Ta)98Si2組細(xì)胞外基質(zhì)的礦化程度與Ti-6Al-4V組相同,二者均明顯高于陰性對照組。(4)合金試樣植入骨中3個月后肉眼觀察:植入物周圍無明顯紅腫、化膿及組織壞死;X線攝片示材料周圍未見明顯透光區(qū),材料與骨組織結(jié)合較好,無明顯密度減低和炎性改變;硬組織切片染色結(jié)果顯示植入體與周圍骨組織結(jié)合良好,(Ti-35Nb-7Zr-5Ta)98Si2組的骨接觸率(77.45%)大于Ti-6Al-4V組(73.31%);力學(xué)推出實驗結(jié)果顯示(Ti-35Nb-7Zr-5Ta)98Si2的骨結(jié)合力(377N)大于Ti-6Al-4V(284N)。結(jié)論:(1)新型超細(xì)晶低彈鈦合金(Ti-35Nb-7Zr-5Ta)98Si2的生物相容性良好,沒有細(xì)胞毒性和組織排斥反應(yīng),是一種安全性良好的生物醫(yī)學(xué)合金。(2)該合金具耐腐蝕性良好、生物活性較高,骨整合能力優(yōu)秀,是有很好應(yīng)用價值的生物醫(yī)學(xué)植入材料。
[Abstract]:Objective: titanium alloy has good biocompatibility and is a common biomedical metal material at present. However, there is still a relatively high elastic modulus and the binding force of the implant and bone in the application process. The difference in the elastic modulus of the implant and bone tissue will cause the poor interfacial stress conduction and influence the regeneration of the surrounding bone tissue. Remodeling, reducing bone density and bone strength, causing bone implants loosening and even failure. A new type of beta titanium alloy with nominal component (Ti-35Nb-7Zr-5Ta) 98Si2 was developed by South China University of Technology. The alloy was designed by D Electronic alloy design theory and produced by discharge plasma sintering (SPS) with low modulus of elasticity (37GPa), high strength and high plasticity And the superfine crystal structure. Among them, the Ti-35Nb-7Zr-5Ta alloy system has been proved to have good biocompatibility and low modulus of elasticity, while silicon (Si) elements have the function of increasing amorphous formation and grain refinement, and also have good compatibility. (Ti-35Nb-7Zr-5Ta) the modulus of elasticity of (Ti-35Nb-7Zr-5Ta) 98Si2 alloy is much lower than that of Ti-6Al-4V. Human bone. The purpose of this study was to evaluate the corrosion resistance, biocompatibility, bioactivity and bone integration of the alloy, and to explore its biological safety and the application value of the Department of orthopedics. Methods: (1) corrosion resistance evaluation: the alloy samples were soaked in 1D, 7d, 14d, 30d, 60d in normal saline. The change of pH value of physiological saline during soaking process, the weight change of the alloy sample before and after immersion and the change of surface morphology under scanning electron microscope, in order to explore its corrosion resistance. (2) biocompatibility evaluation: preparation (Ti-35Nb-7Zr-5Ta) 98Si2 alloy extract culture liquid, L-929 mouse fibroblast culture by leaching solution, through the culture of 1D, 2D, 3D, 5D, 7d. The cell growth state of the cells was observed by light microscopy, and the cytotoxicity of the alloying cells was analyzed by MTT method. The toxicity of the alloying cells was analyzed with the standard of cytotoxicity evaluation of medical materials. The experimental mice were injected with saline solution by intraperitoneal injection to observe the state of 24h, 48h, and 72h after injection of the mice. The acute whole body of the alloy was analyzed according to the total body toxicity evaluation criteria. Toxicity; the alloy specimens were directly applied to the experimental animal skin or intradermal injection of alloy extract, and the local reaction was observed to evaluate the irritation of the skin / skin. The alloy specimens were implanted in the experimental animal bone, and the specimens and their surrounding bone tissues were removed after 3 months, and the hard tissue section, HE staining, microscope observation, and the evaluation of the implant bone group were used to evaluate the implant bone group. The local reaction after weaving. (3) Bioactivity Evaluation: mouse osteoblast MC3T3-E1 and (Ti-35Nb-7Zr-5Ta) 98Si2 alloy specimens were co cultured, 1H, 3h, 6h were stained with acridine orange respectively, the surface adhesion cells were counted under microscope and compared with Ti-6Al-4V alloy, and the effect of the new alloy on osteoblast adhesion was evaluated; and the osteoblasts were compared with the osteoblasts. A total of 24h (Ti-35Nb-7Zr-5Ta) 98Si2 alloy was sprayed on the surface of 98Si2 alloy, and the morphology of adhesion cells was observed under scanning electron microscope; Annexin V-FITC staining osteoblasts and flow cytometry were used to detect the apoptosis rate of cells; ELISA method was used to detect the secretion of interleukin -6/ alkaline phosphatase in osteoblasts, and to evaluate the inflammatory response and 98Si2 coincidence (Ti-35Nb-7Zr-5Ta). The effect of gold on the early differentiation of osteoblast; MC3T3-E1 cells and (Ti-35Nb-7Zr-5Ta) 98Si2 alloy co culture 30d, alizarin red staining of extracellular matrix mineralized nodules, evaluation of the effect of new alloy on the late differentiation of osteoblasts and extracellular matrix mineralization. (4) evaluation of bone integration ability: selected 6 healthy adult New Zealand rabbits as subjects Body weight 2.5~3kg, Ti-6Al-4V and (Ti-35Nb-7Zr-5Ta) 98Si2 alloy were implanted in each femur of each animal, and 3 were implanted in each side of the femur. 3 months after the operation, the animals were treated with the naked eye and X-ray material - the bone interface and the surrounding tissue; the animal femur with the implanted material was taken out of the hard tissue section and Masson staining was performed. The bone binding rate (BCR) was calculated by toluidine blue (1). Results: (1) the material was soaked in 1D, 7d, 14d, 30d, 60d in normal saline, and the pH value of the solution was not significantly changed at all time points; the weight of the alloy samples after soaking was not significantly reduced; through sweep, the weight of the alloy was not significantly reduced. The morphology of the alloy before and after immersion was compared with the surface of the alloy, and the surface finish was similar, and the corrosion resistance was not found. The results showed that the corrosion resistance of (Ti-35Nb-7Zr-5Ta) 98Si2 alloy was good. (2) the L-929 of mouse fibroblasts grew well in the alloy extract, and no obvious cytotoxicity was found, and the cell morphology and ordinary medium were found. There was no difference in cultured cells; MTT test results confirmed that the cytotoxicity of (Ti-35Nb-7Zr-5Ta) 98Si2 alloy was at the level of 0~ I, which accorded with the biosafety standard; the mice intraperitoneally injected with the tested material did not have peritoneum stimulation symptoms, respiratory depression, motor decrease, cyanosis, diarrhoea, tremor and death, which proved that the new alloy did not cause systemic toxicity. There was no local adverse reaction in the experimental animals with surface application and intradermal injection, which proved that the new alloy had no irritation to the skin and skin. After the bone implantation, the bone tissue was not necrotic, and the inflammation and other side effects were not occurring around the alloyed implant. (3) the acridine orange staining results showed the surface of (Ti-35Nb-7Zr-5Ta) 98Si2 alloy. The adhesion cells were not necrotic or apoptotic, and the number of surface adhesion cells was similar to that of Ti-6Al-4V alloy, and there was no significant difference between the two ones. The surface of the osteoblasts showed good growth on the surface of the new alloy by scanning electron microscope. The apoptosis experiment showed that the apoptosis rate of the group of (Ti-35Nb-7Zr-5Ta) 98Si2 gold group was not obvious to the Ti-6Al-4V and negative group. The secretion of interleukin -6 and alkaline phosphatase in osteoblasts was not significantly increased; after the osteoblasts were co cultured with the tested material for 30d, the mineralization degree of the extracellular matrix in (Ti-35Nb-7Zr-5Ta) 98Si2 group was the same as that in the Ti-6Al-4V group, and the two were significantly higher than that in the negative control group. (4) the alloy specimens were implanted in the bone for 3 months after implantation. There was no obvious redness, suppurative and tissue necrosis around the material, and no obvious light transmittance was found around the material. The material and bone tissue were well combined with no obvious density reduction and inflammatory change. The results of hard tissue section staining showed that the implant was well combined with the surrounding bone tissue, and the bone contact rate (77.45%) in group 98Si2 (77.45%) was greater than Ti-6Al-4V Group (73.31%); the experimental results showed that the bone resultant force (377N) of (Ti-35Nb-7Zr-5Ta) 98Si2 was greater than Ti-6Al-4V (284N). Conclusion: (1) the biocompatibility of the new ultra-fine grain low elastic titanium alloy (Ti-35Nb-7Zr-5Ta) 98Si2 is good, there is no cytotoxicity and tissue exclusion reaction, and it is a good biomedical alloy with good safety. (2) the alloy has a good resistance. It has good corrosion resistance, high bioactivity and excellent osseointegration ability. It is a biomedical implant material with good application value.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R318.08;R68

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