本文選題：相轉(zhuǎn)變 + 阿侖磷酸鈉�。� 參考：《浙江大學》2012年碩士論文

【摘要】：磷灰石(Apatite)是人體骨髂的無機礦物質(zhì),主要成分是鈣磷酸鹽和鈣碳酸鹽,含少量的鈉、鎂、和氟化物,多數(shù)以羥基磷灰石的形式存在。同時,這種礦物質(zhì)被普遍認為是幼骨發(fā)育中由其他磷酸鈣鹽前驅(qū)體轉(zhuǎn)化而來。大量研究表明磷酸八鈣(OCP)存在于動物和人體幼骨發(fā)育階段,并且被廣泛視為羥基磷灰石(HA)的重要前驅(qū)體相,在骨的礦化過程中具有重要作用。研究表明,人工合成的OCP比HA具有更為優(yōu)良的生物活性和降解性,并在骨損傷修復中顯示出優(yōu)良的骨傳導和骨誘導特性。另一方面,中老年人群中的骨質(zhì)疏松癥及骨質(zhì)疏松骨折并發(fā)癥問題日益突出,并已成為全球性的重大公共健康問題。目前臨床治療手段主要是服用二膦酸鹽類藥物和富鈣膳食補充劑。二膦酸鹽類藥物給藥方式局限于口服或靜脈注射,其生物利用率較低,并伴隨有明顯的副作用；此外其作用機理也尚不明確,目前的研究大多集中于分子生物學方向,對磷灰石晶體與二膦酸鹽的相互作用研究相對不足。而骨代謝過程中必需的一些微量元素對成骨細胞的增殖、分化和礦化具有良好的促進作用,顯示出優(yōu)良的促進骨再生活性,對開發(fā)新型用于承載治療骨科疾病的藥物體系等方面具有重要意義。如果我們能進一步了解二磷酸鹽、微量元素等對骨礦化初期HA前驅(qū)體的生物學效應機制,勢必會對促進骨質(zhì)疏松性骨折愈合人工修復材料的設(shè)計和構(gòu)建帶來新的啟示。 本文以二膦酸鹽和微量元素與磷酸八鈣晶體的相互作用為研究對象,運用體外礦化體系,系統(tǒng)研究了抗骨質(zhì)疏松藥物阿侖膦酸鈉(AS)以及微量元素(鋅、鍶、鎂)等對OCP形核、生長和相轉(zhuǎn)化的基本規(guī)律,試圖揭示藥物小分子或者磷酸鈣異質(zhì)金屬離子對OCP納米晶生長和相轉(zhuǎn)化的劑量關(guān)系,為骨質(zhì)疏松癥防治臨床用藥和新型顯著促進骨質(zhì)疏松性骨損傷再生特定需求修復用材料的研究開發(fā)建立理論基礎(chǔ)。本文的主要研究結(jié)果如下： 1.考慮到骨礦化過程細胞與外基質(zhì)相互作用特點,本文首先借鑒了細胞膜磷脂雙分子層特征,在體外仿生礦化體系建立中,引入臨界膠束濃度水平的雙親小分子物質(zhì)CTAB。初步探索實驗表明,CTAB存在與否并不影響礦物質(zhì)的沉積時間和相轉(zhuǎn)化效率,但是在CTAB存在條件下磷酸鈣礦物質(zhì)納米晶和其圖簇形態(tài)形貌更為規(guī)整,這極為有利于在顯微條件下考察納米晶形態(tài)演化。因此,后續(xù)研究AS或微量元素介導磷灰石礦物前軀體成核、生長和相轉(zhuǎn)化研究中均存在該臨界膠束濃度水平的雙親小分子物質(zhì)。 2.阿侖膦酸鈉(AS)介導磷灰石礦物質(zhì)前軀體生長的試驗中,我們發(fā)現(xiàn)在較短的陳化時間內(nèi)(無機鹽溶液滴加完成1h后),在極低濃度的AS條件下(2～8μM),在OCP成核條件下卻優(yōu)先出現(xiàn)水合磷酸氫鈣(Dicalcium Phosphate Dihydrate, DCPD)帶狀納米晶,AS越低,這一現(xiàn)象更為顯著；當AS濃度達到16μM后,在陳化1h后礦化沉積產(chǎn)物為羥基磷灰石,并且其納米晶尺度顯著降低,形成高度聚集的納米晶團簇。該實驗結(jié)果表明,AS在極低溶度下就具備顯著調(diào)控磷灰石前軀體相轉(zhuǎn)化的作用。 3.基于上述研究基礎(chǔ),我們進一步探討不同AS濃度水平礦化產(chǎn)物歲陳化時間變化的相轉(zhuǎn)化和形態(tài)演化規(guī)律。結(jié)果發(fā)現(xiàn),在極低AS濃度條件下(2～8μM),DCPD前驅(qū)體穩(wěn)定性逐漸提高,2μM、4μM和8μM AS條件下分別在陳化1、3和8 h候檢測到DCPD的存在；類似地,DCPD在轉(zhuǎn)化為OCP后。在上述AS濃度水平,陳化24、72和168 h候檢測到該相的存在。同時,盡管DCPD和OCP納米晶在溶液中發(fā)生相轉(zhuǎn)化,但是納米晶形態(tài)卻沒有顯著性變化,表明該過程是原位晶相轉(zhuǎn)化,而不是溶解-再結(jié)晶過程。上述研究結(jié)果表明,AS這種抗骨質(zhì)疏松藥物小分子在對幼骨礦物熟化和骨代謝中也具有調(diào)控作用。 4.在針對無機離子調(diào)控磷酸鈣納米晶的實驗研究中,Zn離子濃度在相對Ca離子濃度的2～4‰水平時,則顯示出對磷酸鈣納米晶的形態(tài)和相轉(zhuǎn)化產(chǎn)生促進作用,在較高Sr離子濃度水平(40%),仍然不可見對OCP成核條件下礦化產(chǎn)物的影響。Mg離子作為細胞為基質(zhì)中的宏量元素,我們的研究也顯示該離子在較高水平(10～20%)才會對礦化產(chǎn)物納米晶的形貌與物相產(chǎn)生影響。這些研究結(jié)果表明,不同微量元素對磷灰石前軀體礦化形象存在顯著差異,Zn離子的影響最為突出,Sr離子則難以看到介導磷灰石前軀體相變的影響,說明該無機離子具有穩(wěn)定磷灰石前軀體物質(zhì)的作用。 綜上所述,本論文的主要研究結(jié)果有助于讓我們對具有防治骨質(zhì)疏松癥的二膦酸鹽小分子和骨代謝微量元素等物質(zhì)在直接調(diào)控幼骨發(fā)育和骨骼代謝中的作用的新認識,這對進一步理解二膦酸鹽小分子和骨代謝微量元素的生物學功效以及新型骨質(zhì)疏松性骨損傷材料的設(shè)計和構(gòu)筑方面具有重要意義,同時為骨質(zhì)疏松癥防治用藥劑量、給藥方式等提供有益的知識。
[Abstract]:HA is widely regarded as the important precursor phase of hydroxyapatite ( HA ) , and has become a major global public health problem .
In addition , the mechanism of action is not clear . The current researches focus on the molecular biology direction , and the interaction between apatite crystals and diphosphonate is relatively insufficient . Some trace elements necessary for bone metabolism have a good effect on the proliferation , differentiation and mineralization of osteoblasts .

In this paper , based on the interaction of diphosphonate and trace elements with octaccalcium phosphate crystal , the basic rules of anti - osteoporosis drugs ( AS ) and trace elements ( Zn , Sr , Mg ) and other elements ( Zn , Sr , Mg ) and other elements ( Zn , Sr , Mg ) on the growth and phase transformation of anti - osteoporosis drugs were studied .

1 . Considering the characteristics of the interaction between bone mineralization process cells and outer matrix , the double - parent small molecular substance CTAB with critical micelle concentration level was introduced in this paper . The results showed that the presence or absence of CTAB did not affect the deposition time and phase transformation efficiency of the minerals . However , it was very helpful to study the evolution of nano - crystalline morphology under the condition of CTAB .

2 . In the experiment of Alendronate ( AS ) - mediated precursor growth of apatite , we found that under the condition of low concentration of AS ( 2 - 8 渭M ) , the lower the level of AS ( 2 - 8 渭M ) , the lower the level of AS , the lower the AS , the lower the AS , the lower the AS .
When the concentration of AS reached 16渭m , the mineralization deposit was hydroxyapatite after 1 h of aging , and its nano - crystal size decreased significantly , forming a highly concentrated nanocrystalline cluster . The experimental results show that AS has the function of significantly regulating the transformation of apatite precursor phase at very low solubility .

3 . Based on the above - mentioned research foundation , we further discussed the phase transformation and morphology evolution of the aging time of mineralization products with different concentrations of AS . The results showed that DCPD existed at 1 , 3 and 8 h of aging under extremely low AS concentrations ( 2 - 8 渭M ) , while the stability of DCPD precursor was gradually increased .
Similarly , after conversion of DCPD to ocp , the presence of the phase was detected at the above AS concentration levels , aged 24 , 72 and 168 h . At the same time , despite the phase inversion of DCPD and ocp nanocrystals in solution , there was no significant change in the morphology of the nanocrystals , indicating that the process was in - situ crystallization rather than dissolution - recrystallization .

4 . In the experimental study on the regulation of calcium phosphate nanocrystals with inorganic ions , the effect of Zn ion concentration on the morphology and phase transformation of the calcium phosphate nano - crystal is shown . The results show that the influence of different trace elements on the morphology and phase of the mineralization product under the condition of high Sr ion concentration ( 40 % ) is not visible .

In conclusion , the main results of this paper are helpful for us to understand the role of diphosphonate small molecule and bone metabolism trace elements in the control of immature bone development and bone metabolism directly , which is of great significance for further understanding the biological efficacy of the diphosphonate small molecule and trace elements of bone metabolism and the design and construction of new osteoporosis bone injury materials .
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R318.08

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