本文選題：磷酸鈣骨水泥 + 生物玻璃��； 參考：《第四軍醫(yī)大學》2013年博士論文

【摘要】：我國50歲以上人群中有骨質疏松(Osteoporosis, OP)患者近7000萬，每年新發(fā)脊柱壓縮骨折約181萬例。微創(chuàng)椎體成形術(Vertebroplasty, VP)或球囊擴張椎體后凸成形術(Balloon kphoplasty, BKP)是脊柱壓縮骨折(Vertebral compression fractures, VCF)的主要外科治療手段。VP或BKP中所采用的材料大多數(shù)為聚甲基丙烯酸甲酯（Polymethylmethacrylate, PMMA）。該材料存在明顯缺陷：不可吸收、無生物活性（骨傳導、誘導作用等），固化過程中發(fā)熱明顯等。因此，尋找一種能夠具有良好流動性、骨傳導、骨誘導作用，兼具良好的力學支撐性能及一定降解率的骨修復材料已經(jīng)成為骨科亟待解決的難題。 磷酸鈣骨水泥（Calcium phosphate cement, CPC）因其自固化，無類似PMMA的產(chǎn)熱效應，可任意塑形，良好的生物相容性、骨傳導性及可降解被新生骨替代等特點，具有廣闊的臨床應用價值。然而，CPC在體內降解緩慢。另外，在一些供血不足區(qū)域及伴代謝紊亂的老年病患中，CPC的骨傳導作用并不足以達到完全的骨修復效果，因此賦予CPC更高的傳導性或誘導性可進一步改善其生物學性能。 生物玻璃（Bioactive glass, BG）由于其良好的生物活性和生物相容性倍受關注，生物玻璃與軟組織或骨之間存在密切的離子交換，可直接參與人體骨組織的代謝和修復過程，最終可在材料表面形成與人體骨相同的無機礦物成分——碳酸羥基磷灰石，誘導新生骨組織的生長。將其作為可注射型材料組成成分與CPC復合應用于椎體成形或球囊成形術及不規(guī)則骨缺損如口腔及顱面部等處的骨缺損填充修復的研究鮮見文獻報道。 目的： 優(yōu)選最佳的CPC與BG材料復合比，研發(fā)出一種體內可吸收、具有良好生物相容性及成骨活性的新型可注射生物復合材料。 方法： 1.將CPC與BG以不同質量比混合后，比較其固化時間及可注射性能，篩選出合適的材料復合比； 2.將CPC與BG以選定的材料復合比及固液比混合后，分析其組成成分，微觀結構，固化時間，可注射性能，力學強度及體外生物活性特性和降解性等材料學特性； 3.將大鼠成骨細胞(osteoblasts, OB)接種于材料試件表面，觀察OB在試件表面粘附、增殖和分化能力； 4.將CPC-BG復合生物材料植入新西蘭白兔體內4，12周后，行大體、顯微CT（Micro-computed tomography，Micro-CT）分析和組織學觀察。 結果： 1.隨著BG加入的比例增加（10%,20%,30%,40%），CPC-BG復合生物材料的固化時間延長，可注射性能提高。較單純CPC，CPC-BG組固化時間延長（21min到44min），同時可注射性能顯著提高（P 0.05）； 2. CPC-BG復合生物材料的材料學研究中，X射線衍射分析（X-ray diffraction，XRD）結果顯示CPC及CPC-BG復合生物材料組主要的衍射峰為沉積的羥基磷灰石（Hydroxyapatite, HAp），隨著BG含量從10%升至20%，可出現(xiàn)Ca2SiO4及Ca3SiO5衍射峰，電鏡觀察發(fā)現(xiàn)加入BG后，材料結構更緊密。力學性能方面，固化1天及7天后的材料CPC+20%BG組明顯高于單純CPC組（P 0.05）。體外生物活性實驗結果發(fā)現(xiàn)，浸泡模擬體液（Simulated body fluid, SBF）后，CPC-BG組表面HA沉積量明顯多于CPC。能譜結果（Energy dispersive spectroscopy, EDS）表明，CPC-BG復合材料表面沉積的HA主要由Ca, P及Si組成，而CPC僅含Ca及P元素。體外降解實驗發(fā)現(xiàn)，加入BG后可提高材料降解性； 3.細胞學實驗結果表明，加入BG后，可提高成骨細胞的粘附，增殖及分化。MTT結果顯示，8h后，CPC-BG復合材料組與單純CPC組有統(tǒng)計學差異（P0.05）。隨著時間的延長，細胞進一步增殖，在1d，4d及7d時MTT結果顯示，CPC-BG組優(yōu)于CPC組，其中在4d及7d時，CPC-BG組與CPC組有統(tǒng)計學差異（P 0.05）。堿性磷酸酶活性（Alkaline phosphatase, ALP）檢測發(fā)現(xiàn)，7d時，CPC-BG組與CPC組有統(tǒng)計學差異（P 0.05）； 4.新西蘭白兔體內植入實驗中，大體，Micro-CT和組織學檢測顯示，，在4周和12周，所有材料組的體內降解率和新生骨生成量隨著時間的延長而增加，其中CPC-BG組材料的體內降解率和新生骨生成量均明顯高于CPC組（P 0.05）。 結論： 1．CPC-BG（10%,20%）復合生物材料的固化時間及可注射性符合外科手術要求，隨著BG的增加，復合生物材料的成分、微觀結構發(fā)生了改變，可注射性，力學性能進一步提高，同時，體外生物活性及降解率也有了明顯的改善； 2．將BG引入CPC中，有利于成骨細胞的粘附、增殖和分化； 3．CPC-BG復合生物材料具有優(yōu)秀的生物相容性，更高的生物活性、體內降解率和骨生成率，更有利于骨缺損的修復。
[Abstract]:Nearly 70 million patients with osteoporosis ( OP ) in China over the age of 50 years , with about 1.8 million new vertebral compression fractures per year , are the main surgical treatment methods for vertebral compression fractures ( VCF ) . Most of the materials used in VP or BKP are polymethyl methacrylate ( PMMA ) . The material has obvious defects such as non - absorption , no biological activity ( bone conduction , induction action , etc . ) , obvious heat generation during curing , etc . Therefore , it is difficult to find a bone repairing material which can have good fluidity , bone conduction and osteoinductive effect , and has good mechanical support property and certain degradation rate .


Calcium phosphate cement ( CPC ) has broad clinical application value because of its self - curing , non - PMMA - like heat - producing effect , arbitrary shaping , good biocompatibility , bone conductivity and degradable bone replacement .


Because of its good biological activity and biocompatibility , biological glass ( BG ) can be directly involved in metabolism and repair of bone tissue in human body due to its good biological activity and biocompatibility .


Purpose :


A novel injectable biological composite material with good biocompatibility and osteogenic activity is developed .


Method :


1 . after mixing the CPC and the BG at different mass ratios , comparing the curing time and the injectable performance of the CPC and the BG , and screening out a suitable material composite ratio ;



2 . After mixing CPC and BG with the selected material composite ratio and solid - liquid ratio , the components , microstructure , curing time , injectability , mechanical strength and in vitro biological activity and degradability are analyzed .



3 . inoculating rat osteoblasts ( OB ) on the surface of the material test piece , and observing the adhesion , proliferation and differentiation ability of the OB on the surface of the test piece ;



4 . The CPC - BG composite biomaterial was implanted in New Zealand white rabbit for 4 , 12 weeks , and then was analyzed by micro - computed tomography ( Micro - CT ) and histological observation .


Results :


1 . With the increase of BG addition ( 10 % , 20 % , 30 % , 40 % ) , the curing time of CPC - BG composite biomaterial was prolonged , and the injection performance was improved . Compared with CPC , CPC - BG group had prolonged curing time ( 21min to 44min ) , while the injection performance was improved significantly ( P 0.05 ) .



2 . In the material study of CPC - BG composite biomaterial , X - ray diffraction ( XRD ) results show that the main diffraction peaks of CPC and CPC - BG composite biomaterial groups are deposited hydroxyapatite ( CPC ) . As the BG content increases from 10 % to 20 % , the diffraction peaks of Ca2SiO4 and CaSiO5 can be observed , and the material structure is more compact . In terms of mechanical properties , the CPC + 20 % BG group after curing for 1 day and 7 days is obviously higher than that of the pure CPC group ( P 0.05 ) . The results of in vitro bioassay showed that the HA deposition of CPC - BG group was significantly higher than that of CPC after immersion of simulated body fluid ( SBF ) . Energy dispersive spectroscopy ( EDS ) indicated that the HA of CPC - BG composite was mainly composed of Ca , P and Si , while CPC contained only Ca and P elements .



3 . The results showed that the CPC - BG group was superior to CPC group at 1d , 4d and 7d after addition of BG . The results showed that the CPC - BG group was superior to CPC group at 1d , 4d and 7d after 8 h . The results showed that CPC - BG group had statistical difference with CPC group ( P 0.05 ) . There was significant difference between CPC - BG group and CPC group ( P 0.05 ) .



4 . In vivo implantation experiment of New Zealand white rabbits , in general , Micro - CT and histological examination showed that in both 4 and 12 weeks , the in vivo degradation rate and the amount of new bone formation increased with the extension of time , in which the in vivo degradation rate and the amount of bone formation in CPC - BG group were significantly higher than that of CPC group ( P 0.05 ) .


Conclusion :


1 . The curing time and injectability of CPC - BG ( 10 % , 20 % ) composite biomaterial conform to the surgical requirements . With the increase of BG , the composition and microstructure of the composite biomaterial change , the injectability and the mechanical property are further improved , meanwhile , the in vitro bioactivity and degradation rate are obviously improved ;



2 . introducing BG into CPC , which is beneficial to the adhesion , proliferation and differentiation of osteoblasts ;



3 . The CPC - BG composite biomaterial has excellent biocompatibility , higher biological activity , in vivo degradation rate and bone formation rate , and is more favorable for repairing bone defect .

【學位授予單位】：第四軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2013
【分類號】：R318.08

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