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TWI411595B - 以溫感水膠製備含多孔性陶瓷組合物的方法 - Google Patents

以溫感水膠製備含多孔性陶瓷組合物的方法 Download PDF

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TWI411595B
TWI411595B TW99110691A TW99110691A TWI411595B TW I411595 B TWI411595 B TW I411595B TW 99110691 A TW99110691 A TW 99110691A TW 99110691 A TW99110691 A TW 99110691A TW I411595 B TWI411595 B TW I411595B
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temperature
slurry
porous ceramic
bone
methacrylic acid
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TW201134783A (en
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Chih Kuang Wang
Mei Ling Ho
Yin Chih Fu
Gwo Jaw Wang
Je Ken Chang
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Univ Kaohsiung Medical
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Description

以溫感水膠製備含多孔性陶瓷組合物的方法
本發明關於一種製備含多孔性陶瓷組合物的方法。
先天或後天之骨骼缺損為骨科手術上之一大難題。為了促進骨骼缺損之癒合，大約15%之病患須殖入骨頭(Urist 1994)。自體骨移植由於可以避免傳染疾病及有較高的癒合率，因此為骨頭移殖中最為常用之方式。但自體骨移植亦有其潛在的缺點，如：取骨處之疼痛、可取量較少、尤其是在小孩更是如此(Glowwacki et al 1981,Grob 1986,Dutting et al 1988)。異體骨移植其潛在的缺點如：骨銀行之高成本負擔、較高的疾病傳染率、異體骨斷裂、以及高比率的未癒合，均限制異體骨移植的實用性(Kotani et al 1992)。於1960年代，去蛋白質小牛骨材料被發展出，且被證實是一極具前瞻性之骨頭取代物質(Katthgen and Mittelmeier 1983)。當時所使用之模式為兔子股骨遠端骨踝。而骼崤(iliac crest)與股骨遠端骨踝特點均是富含海綿骨及骨母細胞。此外許多研究表明多孔材料的成骨效果明顯高於緻密材料。孔隙的大小也影響材料的成骨作用，有研究證實，至少100μm的孔隙才有可能使新骨長入。1994年Kuhne等人將不同孔隙的珊瑚HAp植入兔股骨髁，12和26周發現200μm孔隙的材料無新骨長入，500μm孔隙的材料則有新骨長入，說明孔隙的大小可影響材料的成骨作用。對於可降解材料，多孔形態可以增加材料的總面積，促進材料的降解。植入材料中血管長入的速度是影響骨長入和植入材料成功與否的關鍵因素，多孔材料還為血管長入提供了基礎。血管長入帶來了成骨所需的各種因數、間充質細胞、及其它骨生長所需的營養。但將植入材料製成多孔狀，可明顯削弱材料的強度。多孔材料的力學性能遠不及緻密材料，由於這種原因，使用時需考慮移植的位置。
一個良好的骨頭取代物質之先決條件為必須能支撐並促進骨細胞之生長(Doherty et al 1987)。近十幾年來，陸續有許多商品級磷酸鹽類生物陶瓷塊在不同之骨頭缺損處進行臨床應用，市場價值極高。但是對台灣而言目前都仰賴進口，價格一直居高不下。
近來關於不癒合骨缺損、壞死等手術與人工植牙在臨床上已逐漸重要，然欲達到良好的治療效果，則其對於骨組織再生接合或齒槽骨是否足夠便成為關鍵。唯此類手術常需自體骨移植來達成，幸賴生物與材料科技的發展與改進，以骨移植填充材(bone graft fillers)及引導骨組織再生(guided bone regeneration;GBR)的技術等已可助病患重建骨組織的希望。目前使用在人工骨填補材料主要有具生物相容性的生物陶瓷材料、天然或合成的生物高分子材料或其複合材料。
目前已知的多孔性陶瓷生產技術一般為聚合物海绵與陶瓷漿料混合後燒結，其優點是微結構容易控制，但機械強度低且結構較不均勻。另一種技術為凝膠注模成型(Gel casting)，其將陶瓷懸浮體加入單體、引發劑與成形劑的混合物以形成多孔性陶瓷，其優點是具有較高的機械強度，但微結構較差。
本發明欲發展具奈/微米孔隙之多孔性磷酸鈣鹽生物陶瓷複合材料支架(scaffold)，使得體液中養分與新生血管能適時進入此多孔性磷酸鈣鹽生物陶瓷支架中，並達到良好多孔性、製程簡易性且在體內具有部分可吸收性，將來並可與抗發炎或促進骨生長的藥物進行包埋或接枝。故本發明以溫感水膠模板進行多孔性與製程簡易開發，並以雙相磷酸鹽生物陶瓷結構成份來增加生物吸收性。此生物材料使用時尚可與骨髓混合以利用骨髓之骨誘導(osteo-induction)與骨生成(osteo-genesis)之效果而促進骨再生。此可吸收式複合材料更可進而應用於前瞻性的研究，例如：骨科組織工程領域-用以包覆、固定各種不同具骨誘導性的BMP生長因子、血管新生促進因子(VEGF)等或促進骨再生之藥物，如史塔丁(statin)、雙磷酸鹽類(bisphosphanate)等，也可於體外先種入骨細胞、幹細胞，以達到最佳的骨修補效果，或作為抗生素等治療劑之載體，配合釋藥控制技術，治療骨髓炎等骨骼病症。
發明人發現到使用溫感水膠製備多孔性陶瓷有許多優點，如(1)溫感水膠在溫度上升時會有收縮的能力，讓燒結粉體能構緻密化；(2)室溫時溫感水膠為液狀，可進行室溫攪拌製程；(3)溫感水膠不會對羥基磷灰石(HAp)燒結產生相轉變或是細胞毒性；(4)溫感水膠有器孔殘留與微小孔的模板功能；及(5)可再添加第二類成孔劑來製備多孔性。
本發明中所使用的術語『溫感』意指具有能感知冷及熱的能力，以及能感知外部對象的溫度差異。
本發明中所使用的術語『水膠』意指其中液體成分為水的凝膠。水膠在製程上，可以避免化學溶劑而使用大量的水，使其富含水的特性並與活體組織相近，因此可應用在低分子量親油性藥物、親水性藥物的藥物傳輸及不穩定生物分子的傳輸如蛋白質、基因、細胞固定與組織工程上。另外水膠在材質上可同時具備生物相容性與生物可分解性，可進一步應用於體內實驗上。
本發明中所使用的術語『多孔』或『多孔性』意指具有許多可使空氣或水緩慢流通的小洞。
本發明中所使用的術語『陶瓷』意指需高溫處理或致密化的非金屬無機材料，包括矽酸鹽、氧化物、碳化物、氮化物、硫化物、硼化物等等。
本發明中所使用的術語『分散劑』意指促使物料顆粒均勻分散於介質中，形成穩定懸浮體的藥劑。分散劑一般分為無機分散劑和有機分散劑兩大類。常用的無機分散劑有矽酸鹽類(例如水玻璃)和鹼金屬磷酸鹽類(例如三聚磷酸鈉、六偏磷酸鈉和焦磷酸鈉等)。有機分散劑包括三乙基己基磷酸、十二烷基硫酸鈉、甲基戊醇、纖維素衍生物、聚丙烯醯胺、古爾膠、脂肪酸聚乙二醇酯等。
本發明中所使用的術語『高分子』意指通過一定形式的聚合反應而生成的、具有相當高的分子量的大分子。
本發明中所使用的術語『生物材料』意指一种用於醫藥設備的、與生物系統相互作用的非存活性材料。
本發明所使用之詞語『一』或『一種』，其可意指『一個』，但其亦與『一或多個』、『至少一個』及『一個或一個以上』之涵義一致。
本發明所使用之詞語『或』係用以意指『及/或』。
因此，本發明提供一種製備含多孔性陶瓷組合物的方法，其包含步驟如下：
a.　合成氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物(poly(N-isopropylacrylamide-co-methacrylic acid)；p(NIPAAM-MAA))或其類似溫感化合物；
b.　將羥基磷灰石或磷酸鈣鹽類與分散劑混合；
c.　混合步驟a之p(NIPAAM-MAA)或其類似溫感化合物與水以得出膠體溶液；
d.　混合步驟c之膠體溶液與步驟b之產物以得出混合物；
e.　加入高分子顆粒至步驟d之混合物中並攪拌以得出漿體；
f.　將步驟e之漿體填入模板槽中；及
g.　將步驟f之填入漿體的模板槽裝載於陶瓷坩堝中，然後送入高溫爐內進行燒結，以得出含多孔性陶瓷組合物
在較佳實施例中，步驟b之羥基磷灰石或磷酸鈣鹽類與分散劑之重量百分比的範圍係從25：1到25：5；步驟b之分散劑可以為聚丙烯酸鈉鹽(polyacrylic acid；PAA)、聚甲基丙烯酸鈉(polymethacrylic acid；PMA)或聚乙烯醇(poly-vinyl-alcohol；PVA)及其類似物；步驟b之羥基磷灰石或磷酸鈣鹽類係於混合前先由高溫爐燒結至800℃到900℃；步驟c之p(NIPAAM-MAA)水的體積比的範圍係從1：2到2：1；步驟e之高分子顆粒體積係步驟d之混合物總體積之5%到20%；步驟f之模板槽係聚酯纖維多孔模板槽或氧化鋁陶瓷模板槽；步驟g之陶瓷坩堝係氧化鋁材質；步驟g之高溫爐設定為如下之四階段：第一階段：2小時緩慢升溫至600℃到650℃(3到6℃/min)，且持溫30到60分鐘；第二階段：20到30分鐘快速升溫至1150到1250℃(15到25℃/min)，且持溫10到30分鐘；第三階段：10到15分鐘緩慢升溫至1250到1350℃(3到6℃/min)，且持溫1到3小時；及第四階段：利用爐冷使之緩慢降溫至25℃。
在更佳實施例中，上述步驟e之高分子係聚乙烯。
在較佳實施例中，該多孔性陶瓷組合物具有奈米或微米孔隙，可作為生物材料支架，該生物材料支架具有部份生物可吸收性。在更佳實施例中，該生物材料支架係作為人工骨使用，並可與可促進骨再生的物質混合，其中該促進骨再生的物質係選自由骨髓、BMP生長因子、血管新生促進因子、史塔丁(statin)類藥物、雙磷酸鹽(bisphosphanate)類藥物、骨細胞及幹細胞所組成之群組。在另一較佳實施例中，該生物材料支架係作為治療劑之載體。在更佳實施例中，該治療劑係抗生素類藥物。
本發明可能以不同的形式來實施，並不僅限於下列文中所提及的實例。下列實施例僅作為本發明不同面向及特點中的代表。
實施例1 氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物之溫感水膠合成
氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物的化學式如下所示：
將5g(44.2mmole)的氮-異丙基丙烯醯胺(簡稱NIPAM，購自Aldrich)與40μl(0.4mmole)的甲基丙烯酸(簡稱MAA，購自Fluka)置於100毫升的圓底燒瓶中，與30毫升的二次蒸馏水混合攪拌，並置於32℃的水浴環境下。逐一添加0.05g過硫酸銨(Ammoniumpersulfat，簡稱APS，購自Riedel-de Han)與500μl的N,N,N’,N’,-四亞甲二胺(簡稱TEMED，購自Fluka)於圓底燒瓶中均勻攪拌4小時後移除水浴至室溫環境下持續攪拌24小時，之後利用吸量管(pipette)吸取至透析模(Mw:1000)以每隔兩小時替換二次蒸餾水進行為時8小時透析以利將單體排除，進行冷凍乾燥24小時，得粉末產物氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物，室溫保存，產率約為70%到80%。
漿體調配
將先用高溫爐燒結至800℃的羥基磷灰石(簡稱HAp，購自Plasma Biotal Limited)取1.25g，與0.05g分散劑(聚丙烯酸鈉鹽)(簡稱PAA，購自Aldrich)均勻混合於50ml的燒杯中，並將事先調配的氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物與二次蒸餾水體積比為1:1的膠體溶液取1ml至燒杯中，使用均質機混合。最後再取以總體積比5%的聚乙烯顆粒(1000μm)(簡稱PE，購自AJohnson Mathery(Alfa Aesar))約0.12g至燒杯中以手動均勻攪拌。
填模
將調配好的漿體填入聚酯纖維或氧化鋁陶瓷的多孔模板槽中。
高溫燒結
先將高溫爐燒結曲線設定為四階段：第一階段：2小時緩慢升溫至650℃(約5℃/min)，且持溫30分鐘；第二階段：30分鐘快速升溫至1250℃(約20℃/min)，且持溫10分鐘；第三階段：10分鐘緩慢升溫至1300℃(約5℃/min)，且持溫2小時；及第四階段：利用爐冷使之緩慢降溫至25℃。
高溫爐設定完畢後將漿體與模具裝載於氧化鋁材質的陶瓷中送入高溫爐內執行燒結步驟。
氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物之合成與分析如圖1到圖4所示。多孔羥基磷灰石燒結過後的成像與分析則如圖5到圖8所示。
一個熟知此領域技藝者能很快體會到本發明可很容易達成目標，並獲得所提到之結果及優點，以及那些存在於其中的東西。本發明中之化合物、組合物、混合物及其製造程序與方法乃較佳實施例的代表，其為示範性且不僅侷限於本發明領域。熟知此技藝者將會想到其中可修改之處及其他用途。這些修改都蘊含在本發明的精神中，並在申請專利範圍中界定。
本發明的內容敘述與實施例均揭示詳細，得使任何熟習此技藝者能夠製造及使用本發明，即使其中有各種不同的改變、修飾、及進步之處，仍應視為不脫離本發明之精神及範圍。
說明書中提及之所有專利及出版品，都以和發明有關領域之一般技藝為準。所有專利和出版品都在此被納入相同的參考程度，就如同每一個個別出版品都被具體且個別地指出納入參考。
在此所適當地舉例說明之發明，可能得以在缺乏任何要件，或許多要件、限制條件或並非特定為本文中所揭示的限制情況下實施。所使用的名詞及表達是作為說明書之描述而非限制，同時並無意圖使用這類排除任何等同於所示及說明之特點或其部份之名詞及表達，但需認清的是，在本發明的專利申請範圍內有可能出現各種不同的改變。因此，應了解到雖然已根據較佳實施例及任意的特點來具體揭示本發明，但是熟知此技藝者仍會修改和改變其中所揭示的內容，諸如此類的修改和變化仍在本發明之申請專利範圍內。
圖1顯示溫感水膠p(NIPAAM-MAA)之合成示意圖。
圖2顯示溫感水膠p(NIPAAM-MAA)於37℃從溶膠轉換成凝膠的示意圖。
圖3顯示NIPAAM單體與p(NIPAAM-MAA)共聚高分子之1 H NMR光譜圖分析。證明出NIPAAM單體上雙鍵被加成聚合後已消失。
圖4顯示NIPAAM單體(上)與p(NIPAAM-MAA)共聚高分子(下)之FTIR光譜圖分析。證明出p(NIPAAM-MAA)共聚高分子之COOH是MAA上的官能基。
圖5顯示以溫感水膠p(NIPAAM-MAA)共聚高分子模板製成之多孔性羥基磷灰石生物陶瓷的巨觀相片。
圖6顯示以溫感水膠p(NIPAAM-MAA)共聚高分子模板製成之多孔性羥基磷灰石生物陶瓷的微觀SEM相片(上下圖呈現出大小微孔，顯示其具有微奈米孔洞)。
圖7顯示以溫感水膠p(NIPAAM-MAA)共聚高分子模板製成之多孔性羥基磷灰石生物陶瓷之FTIR分析。從圖中可看出OH官能基已損失。
圖8顯示以溫感水膠p(NIPAAM-MAA)共聚高分子模板製成之多孔性羥基磷灰石生物陶瓷(產品)與純羥基磷灰石(純的)之XRD分析比較。圖中可看出相結構主要是磷灰石結構，但少部分有β-TCP結構(主要峰Hap；次要峰β-TCP)。

Claims (6)

  1. 一種製備含多孔性陶瓷組合物的方法，其包含步驟如下：a.合成氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物(poly(N-isopropylacrylamide-co-methacrylic acid)；b.將羥基磷灰石或磷酸鈣鹽類與分散劑以重量百分比範圍從25：1到25：5的比例混合，其中該分散劑為聚丙烯酸鈉鹽(polyacrylic acid；PAA)、聚甲基丙烯酸鈉(polymethacrylic acid；PMA)或聚乙烯醇(poly-vinyl-alcohol；PVA)；c.混合步驟a之氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物與水以得出膠體溶液，其中氮-異丙基丙烯醯胺-甲基丙烯酸共聚合物與水的體積比的範圍係從1：2到1：1；d.混合步驟c之膠體溶液與步驟b之產物以得出混合物；e.加入高分子顆粒至步驟d之混合物中並攪拌以得出漿體，其中該高分子係聚乙烯，其顆粒體積係步驟d之混合物總體積之5%到20%；f.將步驟e之漿體填入模板槽中；及g.將步驟f之填入漿體的模板槽裝載於陶瓷坩堝中，然後送入高 溫爐內以600℃至1350℃進行燒結，以得出含多孔性陶瓷組合物。
  2. 根據申請專利範圍第1項之方法，其中步驟b之羥基磷灰石或磷酸鈣鹽類係於混合前先由高溫爐燒結至800℃到900℃。
  3. 根據申請專利範圍第1項之方法，其中步驟f之模板槽係聚酯纖維多孔模板槽或氧化鋁陶瓷模板槽。
  4. 根據申請專利範圍第1項之方法，其中步驟g之陶瓷坩堝係氧化鋁材質。
  5. 根據申請專利範圍第1項之方法，其中步驟g之高溫爐設定為如下之四階段：第一階段：2小時緩慢升溫至600℃到650℃(3到6℃/min)，且持溫30到60分鐘；第二階段：20到30分鐘快速升溫至1150到1250℃(15到25℃/min)，且持溫10到30分鐘；第三階段：10到15分鐘緩慢升溫至1250到1350℃(3到6℃/min)，且持溫1到3小時；及第四階段：利用爐冷使之緩慢降溫至25℃。
  6. 根據申請專利範圍第1項之方法，其中該多孔性陶瓷組合物具有奈米或微米孔隙。
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