本文選題：磷酸鈣骨水泥 + 電紡纖維　； 參考：《西南交通大學(xué)》2014年碩士論文

【摘要】：磷酸鈣骨水泥(Calcium Phosphate Cements, CPC)因具有良好的生物相容性、骨傳導(dǎo)性和可注射性,已作為骨替代材料應(yīng)用于臨床,此外其制備過程中避免了高溫?zé)Y(jié)工藝,適合作藥物和生物活性因子等的載體。但由于CPC易脆、強(qiáng)度低和降解速率慢,只能用在非承重部位且不利于骨組織的生長(zhǎng)。纖維常通過橋聯(lián)、拉拔、負(fù)荷傳遞等作用增強(qiáng)無機(jī)材料的力學(xué)性能。電紡纖維制備方法簡(jiǎn)單經(jīng)濟(jì),且與細(xì)胞外基質(zhì)的形態(tài)結(jié)構(gòu)相似,已被廣泛應(yīng)用于組織工程。因此,本論文的目的是利用載阿侖膦酸鈉(ALN)電紡聚乳酸-羥基乙酸共聚物(PLGA)纖維增韌CPC,同時(shí)實(shí)現(xiàn)ALN的局部控釋。此外ALN還作為改善PLGA纖維在CPC中潤(rùn)濕性的“表面活性劑”。載ALN的PLGA纖維植入機(jī)體后可降解形成孔隙,促進(jìn)新骨的生長(zhǎng),從而更好的滿足其臨床需求。 采用靜電紡絲技術(shù)分別制備PLGA纖維和載藥PLGA纖維。通過掃描電鏡(SEM)、酶標(biāo)儀和接觸角測(cè)試儀等測(cè)定纖維的形貌、尺寸、載藥率及接觸角等。選用Biocement D磷酸鈣骨水泥配方,以磷酸鹽緩沖液為液相,液固比為0.45mL/g,將PLGA纖維與CPC混合制備含不同百分含量PLGA纖維CPC,并通過X射線衍射(XRD)、Gillmore雙針法、力學(xué)性能測(cè)試以及SEM檢測(cè)含PLGA纖維CPC的相成分、凝固時(shí)間、力學(xué)性能和表面形貌等。采用正交實(shí)驗(yàn)優(yōu)化及分析定向和非定向PLGA纖維、非載藥和載藥PLGA纖維及PLGA纖維含量對(duì)CPC力學(xué)性能的影響,并研究最優(yōu)組表面形貌、凝固時(shí)間、相成分、體外降解及藥物釋放動(dòng)力學(xué)等。此外,采用與成骨細(xì)胞(MC3T3-E1)共培養(yǎng)研究各組CPC上細(xì)胞黏附、增殖及分化的能力。 PLGA形貌分析表明：纖維表面光滑、分布均勻、持續(xù)且纖維彼此分離,空白PLGA纖維和載藥PLGA纖維的平均直徑分別為1.25±0.18μm和1.16±0.2μmALN的加入并未改變纖維的形貌及尺寸,但減少了纖維的疏水性,接觸角由116.8±2.3°降低到94.1±2.5°,藥物的包封率可達(dá)到56.20±0.99%。 含PLGA纖維CPC力學(xué)性能測(cè)試表明：PLGA纖維的加入可提高CPC彎曲強(qiáng)度、彈性模量,并能顯著性提高其韌性,且隨著PLGA纖維含量的增加其韌性不斷顯著提高。正交實(shí)驗(yàn)表明最優(yōu)組合為7wt.%非定向載藥PLGA纖維CPC。ALN可改善PLGA纖維在CPC中的潤(rùn)濕性,從而改善PLGA纖維與CPC結(jié)合,進(jìn)一步顯著性提高CPC的韌性。材料斷口形貌及材料的載荷位移曲線分析表明載藥PLGA纖維的加入明顯改變了CPC的斷裂方式,由脆性斷裂變?yōu)闇?zhǔn)脆性斷裂。CPC由脆性材料變?yōu)闇?zhǔn)脆性材料。Gillmore雙針法測(cè)試和相成分結(jié)果顯示：與空白CPC相比,非載藥PLGA纖維和載藥PLGA纖維均降低了CPC的初凝和終凝時(shí)間。物相分析結(jié)果表明加入非載藥PLGA纖維或載藥PLGA纖維到CPC中,阻礙a-TCP和DCPD的轉(zhuǎn)化,但CPC水化終產(chǎn)物主要為a-TCP和HA以及少量的DCPD和CaCO3。 含載藥PLGA纖維CPC的藥物釋放動(dòng)力學(xué)顯示第1天的藥物釋放較快(釋放量達(dá)10%),而隨后藥物釋放較緩慢,因此可大致分為突釋和緩釋兩個(gè)階段。藥物釋放動(dòng)力學(xué)符合Higuchi擴(kuò)散釋放模型,持續(xù)釋放90天藥物累積釋放量約為89%。XRD檢測(cè)結(jié)果顯示,釋放90天后CPC中的物相主要為HA；紅外分析及SEM檢測(cè)證明載藥PLGA纖維完全降解,且降解后在CPC中留下孔隙。各組CPC與成骨細(xì)胞共培養(yǎng)后,活細(xì)胞熒光染色和SEM結(jié)果表明：各組CPC樣品表面都黏附大量的成骨細(xì)胞,成骨細(xì)胞主要呈多邊形,具有強(qiáng)烈的立體感并形成大量的細(xì)胞連接。細(xì)胞周圍伸展出大量偽足,通過偽足與樣品表面緊密黏附,呈現(xiàn)良好的細(xì)胞活性。Almar Blue和堿性磷酸酶(ALP)檢測(cè)分析結(jié)果表明：各組CPC均呈現(xiàn)有較好的成骨細(xì)胞增殖及分化能力,尤其是載藥PLGA纖維CPC,釋放出促進(jìn)骨組織生長(zhǎng)藥物ALN,呈現(xiàn)更好的細(xì)胞分化能力。 本研究制備了含載藥PLGA纖維CPC,載藥PLGA纖維能顯著提高CPC韌性,同時(shí)可實(shí)現(xiàn)藥物的長(zhǎng)時(shí)間可持續(xù)局部控釋,促進(jìn)骨組織生長(zhǎng)。因此載藥PLGA纖維CPC適合作為骨填充材料。
[Abstract]:Calcium Phosphate Cements (CPC), because of its good biocompatibility, bone conductivity and injectable, has been used as a bone substitute for clinical application. In addition, it avoids the high temperature sintering process and is suitable for the carrier of drugs and bioactive factors. But because CPC is brittle, low in strength and slow in degradation rate. It can only be used in non load-bearing parts and is not conducive to the growth of bone tissue. The mechanical properties of inorganic materials are enhanced by the effects of bridging, drawing and load transfer. The preparation of electrospun fibers is simple and economical, and is similar to the morphological structure of the extracellular matrix. Sodium lendronate (ALN) toughened CPC by electrospun poly (lactic acid hydroxy acetic acid) copolymer (PLGA) fiber and locally controlled release of ALN. In addition, ALN is also used as a "surfactant" to improve the wettability of PLGA fibers in CPC. The ALN's PLGA fibers can be degraded to form pores and promote the growth of new bone, so as to better meet their clinical needs.
PLGA fibers and drug loaded PLGA fibers were prepared by electrostatic spinning technology. The morphology, size, drug loading rate and contact angle of the fibers were measured by scanning electron microscopy (SEM), enzyme labeling instrument and contact angle tester. The formula of Biocement D calcium phosphate cement was selected, the phosphate buffer solution was liquid phase and the liquid to solid ratio was 0.45mL/g, and the PLGA fiber was mixed with CPC. PLGA fiber CPC with different percentage content was prepared by X ray diffraction (XRD), Gillmore double needle method, mechanical properties test and SEM detection of phase composition of PLGA fiber CPC, solidification time, mechanical properties and surface morphology. Orthogonal experiment was used to optimize and analyze directional and non directional PLGA fiber, non carrier and drug carrying PLGA fiber and PLGA fiber content. The effects on the mechanical properties of CPC were studied, and the surface morphology, solidification time, phase composition, in vitro degradation and drug release kinetics were studied. In addition, the ability of cell adhesion, proliferation and differentiation on CPC was studied by co culture with osteoblast (MC3T3-E1).
The PLGA morphology analysis shows that the fiber surface is smooth, the distribution is uniform, and the fiber is separated from each other. The average diameter of the blank PLGA fiber and the drug loaded PLGA fiber is 1.25 + 0.18 mu m and 1.16 + 0.2 mu mALN, respectively, but the fiber's water thinability is reduced, the contact angle is reduced from 116.8 + 2.3 to 94.1 + 2.5 degrees. The encapsulation efficiency of the drug can reach 56.20 + 0.99%.
The mechanical properties test of CPC containing PLGA fiber shows that the addition of PLGA fiber can improve the flexural strength, modulus of elasticity of CPC, and improve its toughness remarkably, and with the increase of PLGA fiber content, the toughness is continuously improved. The orthogonal experiment shows that the optimal combination of 7wt.% non directional carrier PLGA fiber CPC.ALN can improve the performance of PLGA fiber in CPC. Wettability, thus improving the combination of PLGA fiber and CPC, and further significantly improving the toughness of CPC. Analysis of fracture morphology and load and displacement curves of material shows that the addition of drug PLGA fiber obviously changes the fracture mode of CPC, from brittle fracture to quasi brittle fracture.CPC from brittle material to quasi brittle material.Gillmore double needle method test. The results of the phase composition show that compared with the blank CPC, the non loaded PLGA fibers and the drug loaded PLGA fibers both reduce the initial and final setting time of the CPC. The results of phase analysis show that the addition of non loaded PLGA fiber or PLGA fiber to CPC prevents the conversion of a-TCP and DCPD, but CPC hydration end products are mainly a-TCP and HA, and a small amount of CPC.
The drug release kinetics of the drug loaded PLGA fiber CPC showed that the release of the drug was faster in first days (10%), and the subsequent release of the drug was slow, so it could be roughly divided into two stages of sudden release and sustained release. The drug release kinetics accorded with the Higuchi diffusion release model, and the cumulative release of the drug for 90 days was about the result of the detection of the drug. 90 days after release, the phase of CPC was mainly HA; infrared analysis and SEM test showed that the drug PLGA fiber was completely degraded, and the pores were left in CPC after degradation. After co culture of CPC and osteoblasts in each group, the fluorescent staining of living cells and the results of SEM showed that the surface of CPC samples adhered to a large number of osteoblasts, and the osteoblasts were mainly multilateralism It has a strong sense of stereoscopic and a large number of cell connections. A large number of pseudo feet are extended around the cells, and the cells are closely adhered to the surface of the sample by the pseudo foot. The results show that the good cell activity.Almar Blue and alkaline phosphatase (ALP) detection and analysis show that all groups of CPC have a better ability of osteoblast proliferation and differentiation, especially the load. The drug PLGA fiber CPC released ALN, which promoted bone tissue growth, and showed better cell differentiation ability.
In this study, the drug loaded PLGA fiber CPC was prepared, and the drug loaded PLGA fiber could significantly improve the toughness of the CPC. At the same time, the long-term local controlled release of the drug could be realized and the growth of bone tissue was promoted. Therefore, the drug loaded PLGA fiber CPC was suitable as a bone filling material.
【學(xué)位授予單位】：西南交通大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R318.08

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本文編號(hào)：2031014