劉瑩，楊瑞，劉井來(lái)，劉佳欣，張靖羚

單相、雙相及多相離子摻雜的羥基磷灰石研究進(jìn)展

劉瑩1a，楊瑞1b，劉井來(lái)2，劉佳欣1b，張靖羚1b

（1.遼寧工程技術(shù)大學(xué) a.理學(xué)院 b.材料科學(xué)與工程學(xué)院，遼寧 阜新 123000；2.甘李藥業(yè)股份有限公司，北京 101102）

羥基磷灰石是天然骨組織成分中的重要組成部分，一直是生物醫(yī)學(xué)領(lǐng)域關(guān)注和研究的重點(diǎn)。天然骨成分中的磷灰石，是一種結(jié)合著多種離子的羥基磷灰石，維持著生命系統(tǒng)的正常生長(zhǎng)與發(fā)育。本研究闡述了羥基磷灰石的晶體結(jié)構(gòu)；概述了研究者針對(duì)羥基磷灰石性能探究，其中包括生物相容性、生物活性、適宜的機(jī)械強(qiáng)度、優(yōu)異的成骨性能和耐腐蝕性能。同時(shí)歸納了離子摻雜羥基磷灰石取代位點(diǎn)。在此基礎(chǔ)上，重點(diǎn)闡述了近五年來(lái)單相、雙相以及多相摻雜羥基磷灰石材料的研究，其中包括單相、雙相以及多相離子摻雜對(duì)羥基磷灰石在結(jié)構(gòu)性能、機(jī)械強(qiáng)度、抗菌性、降解性和成骨性等性能的影響，同時(shí)簡(jiǎn)單總結(jié)了離子摻雜對(duì)機(jī)械強(qiáng)度的影響規(guī)律。近年來(lái)雖然羥基磷灰石生物陶瓷材料在臨床上作為植入物涂層、緩釋藥物的載體、骨移植物代替材料等被應(yīng)用，但在臨床方面廣泛運(yùn)用還面臨著許多問(wèn)題與挑戰(zhàn)，所以本文同時(shí)展望了離子摻雜羥基磷灰石未來(lái)的的發(fā)展方向，有望在臨床應(yīng)用及發(fā)展方面有一定的指導(dǎo)意義。

羥基磷灰石；離子摻雜；抗菌性；機(jī)械強(qiáng)度；植入物涂層；治療癌癥

羥基磷灰石（HA，Ca10(PO4)6(OH)2）是一種與哺乳動(dòng)物硬組織組成非常相似的合成生物陶瓷材料，因此被廣泛應(yīng)用于骨移植、骨修復(fù)、硬組織工程支架和金屬基材的涂層等方面[1-2]。HA中鈣磷比為1.67，晶型常態(tài)屬于六方晶系，穩(wěn)定相為單斜晶相（一般高溫?zé)崽幚砗螅琇6PC對(duì)稱型和63/空間群。晶胞參數(shù)為==0.943～0.938 nm，=0.688～0.686 nm，==90°，=120°，每個(gè)晶胞中包含10個(gè)Ca2+、6個(gè)PO43?和2個(gè)OH?，圖1為HA晶體結(jié)構(gòu)示意圖。

圖1 HA晶體結(jié)構(gòu)示意圖

早在1951年，RD Ray等合成了適用于骨缺損治療領(lǐng)域的HA；直至1980年，de K Groot等相繼合成了HA，并應(yīng)用于整形外科[3]。人工合成的HA具有良好的生物活性、生物相容性、適宜的機(jī)械強(qiáng)度、成骨性和耐腐蝕性等[4]。王艷玲等[5]通過(guò)微弧氧化法在金屬鈦無(wú)牙區(qū)種植體表面制備了HA涂層，發(fā)現(xiàn)HA可以促進(jìn)成骨細(xì)胞的黏附和外周骨質(zhì)的生成，從而誘導(dǎo)骨的形成。T. M等[6]通過(guò)射頻磁控濺射法在AZ91鎂合金表面制備了HA涂層，研究發(fā)現(xiàn)涂層可以控制降解速率，提高AZ91合金的生物相容性和生物礦化能力。楊蕾等[7]利用微弧氧化技術(shù)（MAO）在AZ31鎂合金表面制備出含有納米級(jí)別的n-HA涂層，該涂層能對(duì)多孔形態(tài)進(jìn)行填充，體現(xiàn)優(yōu)異的耐腐蝕效果，在體外細(xì)胞培養(yǎng)實(shí)驗(yàn)中，細(xì)胞粘附和細(xì)胞誘導(dǎo)效果明顯強(qiáng)于無(wú)涂層的樣品，能夠促進(jìn)成骨細(xì)胞的增殖分化。Jiang等[8]通過(guò)水熱法在鈦合金表面覆蓋了一層HA涂層，研究發(fā)現(xiàn)涂層樣品耐蝕性優(yōu)于未涂層樣品，因此植入材料具有良好的生物相容性和骨誘導(dǎo)性。但是HA涂層的脆性和不易降解性限制了其應(yīng)用[9-10]。

研究發(fā)現(xiàn)，生物體內(nèi)的磷灰石是一種晶體結(jié)構(gòu)不完善的HA，其中結(jié)合一些很多微量元素，例如Na+、Mg2+、Zn2+、Cl?、CO32?、F?等離子[11-12]，因此研究者們?cè)谌斯ず铣蒆A時(shí)會(huì)有選擇性的摻入一些離子，通過(guò)離子半徑的變化改變晶格參數(shù)，從而在模擬生物礦化的基礎(chǔ)上改進(jìn)HA的各項(xiàng)性能。

離子摻雜可以分為陰離子摻雜與陽(yáng)離子摻雜。陽(yáng)離子摻雜是指HA中的Ca2+可被某些二價(jià)的陽(yáng)離子（如Mg2+[13-15]、Zn2+[16-19]、Sr2+[20-23]、Fe2+[24-27]、Cu2+[28-32]、Ni2+[33-34]等）部分或全部取代，也可被單價(jià)和三價(jià)的陽(yáng)離子（如Na+[35-37]、K+[35,38]、Fe3+ [24-25,39]、Eu3+[40-44]等）部分取代。陰離子摻雜可分為A和B兩種類型的取代，A是在羥基位點(diǎn)的取代，一般為OH?被Cl?、F?[45-46]、Br?等離子的取代；而B則是PO43?被CO32?[24,44-45]、VO43?[46-47]和SiO44?[48]等部分或全部取代，此取代方式為磷酸根位點(diǎn)的取代，當(dāng)然A、B同時(shí)取代也是存在的。研究者們通過(guò)單相摻雜綜合分析，對(duì)雙相及多相離子摻雜的HA進(jìn)行了多方向多角度的設(shè)想、制備與研究。

本文選材多為離子摻雜HA作為涂層材料改善金屬植入物性能的研究，以更好地滿足骨移植和骨修復(fù)領(lǐng)域的臨床需求。合金材料表面附著的離子摻雜HA涂層材料，為合金材料提供機(jī)械強(qiáng)度和可降解性能，而離子摻雜在通過(guò)改變HA涂層結(jié)構(gòu)和調(diào)控涂層與合金之間的關(guān)系來(lái)增強(qiáng)植入物的生物活性、生物相容性和抗菌性等生物性能。

1 單相離子摻雜羥基磷灰石的制備與發(fā)現(xiàn)

目前，關(guān)于單相離子摻雜已經(jīng)形成系統(tǒng)的研究，下面簡(jiǎn)單對(duì)幾種常見且代表性較強(qiáng)的單相離子摻雜HA的案例進(jìn)行敘述。

M等[45]通過(guò)低溫共沉淀法和水熱輔助溶膠凝膠法相結(jié)合分別制備了HApMn、HApFe、HApCo、HApNi、HApCu、HApZn和純HAp，發(fā)現(xiàn)HAp-Mn、HAp-Fe和HAp-Ni與CaHAp相的PDF文件(00- 009-0432)一致，當(dāng)Mn4+、Fe2+加入與CaHAp相對(duì)應(yīng)的主峰強(qiáng)度降低，而當(dāng)Co+、Cu2+和Zn2+加入時(shí)主峰相發(fā)生偏移至2=26.04°，說(shuō)明離子的加入在一定程度會(huì)降低羥基磷灰石的結(jié)晶度。研究表明離子的加入一般會(huì)降低HA的結(jié)晶度，但均無(wú)其他雜相存在（見圖2）。Mg2+摻雜HA可以促進(jìn)骨和血管形成[46-47]，對(duì)銅綠假單胞菌、金黃色葡萄球菌和白色念珠菌有較好的的抗菌功效，但Mg-HA在形成涂層的過(guò)程中存在著穩(wěn)定性較差的弱點(diǎn)[48]。Fe2+摻雜會(huì)使HA納米粒子具有超順磁性，通過(guò)外加磁場(chǎng)力的作用可以促進(jìn)降解和推動(dòng)礦化過(guò)程，從而促進(jìn)細(xì)胞的增殖與 分化[49-52]。

圖2 CaHA、HAMn、HAFe、HACo、HANi、HACu和HAZn的X射線衍射圖譜[45]

Balak等[53]通過(guò)水熱法制備純HA和Fe-HA（Fe2+為變量），發(fā)現(xiàn)Fe2+的加入改善了HA的晶粒尺寸，最小的尺寸可達(dá)19.7 nm，顯現(xiàn)為球形結(jié)構(gòu)（見圖3）。磁性測(cè)試發(fā)現(xiàn)Fe-HA飽和磁化強(qiáng)度最強(qiáng)為0.029 emu/g；但是微量Fe的加入可能會(huì)產(chǎn)生輕微的溶血現(xiàn)象，以及研究中只體現(xiàn)了硬度的改善，不足以體現(xiàn)Fe2+的加入提高了HA的力學(xué)性能。

Yazici等[54]采用MAO技術(shù)在可降解的Mg-Sr-Ca合金表面制備了Ag-HA涂層。該涂層具有良好的生物活性和耐腐蝕性能，Ag+的增加明顯增強(qiáng)了HA涂層的抑菌性，但抗菌實(shí)驗(yàn)中抗菌率達(dá)到100%時(shí)，Ag+的濃度已經(jīng)超過(guò)其在生物體中的極限濃度，會(huì)產(chǎn)生嚴(yán)重的細(xì)胞毒性。而且在體液浸泡實(shí)驗(yàn)中，隨著Ag+濃度的增加，表面沉積的Sr-HA與Ag-HA之間可能存在應(yīng)力作用，使涂層表面出現(xiàn)了明顯的裂紋。

Taolei等[55]采用水熱法在ZK60鎂合金表面制備了Sr-HA納米棒/納米線涂層。ZK60鎂合金為植入物提供了良好的可生物降解性，Sr-HA涂層具有較好的耐腐蝕性能，Sr2+的存在提高了HA涂層的成骨性和生物相容性。但是水熱法合成的HA與鎂合金之間是否存在應(yīng)力缺陷還值得考究。

Sergi等[56]采用前驅(qū)體等離子噴涂法制備了鋅摻雜羥基磷灰石涂層（Zn-HA），發(fā)現(xiàn)Zn-HA涂層對(duì)人成骨細(xì)胞Saos-2細(xì)胞無(wú)細(xì)胞毒性，對(duì)金黃色葡萄球菌（）和大腸桿菌（）均表現(xiàn)出較強(qiáng)的抗菌作用（見圖4）。

圖3 水熱合成的HA與10FeHA的形貌[53]

Zhou等[57]采用水熱法在ZK60鎂合金表面制備了Zn-HA涂層。研究發(fā)現(xiàn)鋅的加入改變了鍍層的形貌，使其表面出現(xiàn)了納米晶須結(jié)構(gòu)，并發(fā)現(xiàn)此植入物具有良好的成骨分化能力、抑菌能力和耐腐蝕特性。但是Zn2+的摻入量明顯影響HA的穩(wěn)定性，過(guò)量會(huì)有α-磷酸三鈣相存在，這個(gè)結(jié)果可能與溫度有關(guān)[58-59]。

Benjamín等[60]采用水熱法制備了Si-HA。研究發(fā)現(xiàn)Si-HA的結(jié)晶度較高，呈現(xiàn)為35～80 nm的棒狀結(jié)構(gòu)，當(dāng)SiO44?達(dá)到一定濃度時(shí)，高溫?zé)Y(jié)后的HA顆粒之間會(huì)出現(xiàn)SiO2的小玻璃區(qū)域。但Si的實(shí)際摻入量?jī)H為目標(biāo)摻入量的60%左右，并且沒(méi)有表明小玻璃區(qū)域出現(xiàn)對(duì)涂層性能的影響。

Maryam等[61]采用熱物理混合燒結(jié)法制備了SiO2-HA，發(fā)現(xiàn)有SiO44?摻入到HA中，得到的結(jié)論是適當(dāng)?shù)腟i摻雜量會(huì)提高HA的生物可降解能力和礦化能力，原因是制備過(guò)程中有溶解度高于HA的磷酸三鈣（TCP）和硅酸鈣（Ca2SiO4）相的產(chǎn)生，使得到的類羥基磷灰石材料致密性增強(qiáng)。但物理混合法可能會(huì)導(dǎo)致材料部分位置存在應(yīng)力缺陷，且在燒結(jié)過(guò)程中溫度變化對(duì)SiO2-HA產(chǎn)生的Si-HA的分解程度不明確。還有研究發(fā)現(xiàn)Si-HA涂層具有較好的生物活 性[62]，它可以增強(qiáng)成骨細(xì)胞活性，同時(shí)降低破骨細(xì)胞活性，說(shuō)明Si-HA能減緩破骨細(xì)胞分化和骨重塑速率，這對(duì)骨質(zhì)疏松癥有著十分重要的意義[63]。

Nasker等[64]采用水熱法制備了不同濃度氟摻雜n-HA(F-HA)和純n-HA，合成的納米顆粒形貌大多呈均勻規(guī)則的納米棒狀，雖然有氟化鈣雜相出現(xiàn)，但是F?的存在顯著的改善了n-HA的結(jié)晶度與結(jié)構(gòu)穩(wěn)定性，還發(fā)現(xiàn)F-HA有一定的殺菌效果并且粉末無(wú)細(xì)胞毒性（見圖5）。而且F?摻雜n-HA在一定程度上可增加成骨細(xì)胞活性，促進(jìn)骨細(xì)胞生長(zhǎng)、增殖與分化，從而起到誘導(dǎo)骨形成的作用[65-66]。

碳酸根摻雜HA(CHA)，CO32?可以取代OH?或PO43?分別進(jìn)行A或B取代，也可以同時(shí)進(jìn)行AB取代，研究發(fā)現(xiàn)人工合成的CHA一般以B取代為主[67-68]。CO32?取代可以降低HA的結(jié)晶度和熱穩(wěn)定性，提高HA的溶解性[69]，CO32?摻雜羥基磷灰石塊體和涂層樣品在模擬生理溶液中均可形成類骨碳酸羥基磷灰石礦化層[70]。

上述單相離子摻雜HA可以在一定程度上修飾HA的性能，但還不能滿足臨床應(yīng)用的需求，筆者認(rèn)為尚有下述問(wèn)題需要解決：（1）在產(chǎn)物為純相的前提下，結(jié)晶度和晶粒尺寸是否均可被改善；（2）抗菌性作用是否可以同時(shí)高效針對(duì)多種細(xì)菌；（3）生物可降解性是否可以調(diào)控；（4）離子摻雜是否可以有效改善HA的脆性。

這些問(wèn)題可以在單相離子摻雜HA的基礎(chǔ)上，通過(guò)調(diào)整制備工藝、反應(yīng)物濃度和反應(yīng)條件等來(lái)探究，與此同時(shí)為得到優(yōu)良的綜合性能，嘗試復(fù)合離子摻雜HA也已經(jīng)成為了研究的熱點(diǎn)。

圖5 48 h內(nèi)各個(gè)樣品在E.coli和S.aureus兩種菌株存在環(huán)境中的培養(yǎng)情況[64]

Fig.5 The culture situation of each sample in the presence of E.coli and S.aureus within 48 h[64]

2 雙相離子摻雜羥基磷灰石的發(fā)展與應(yīng)用

基于現(xiàn)代生物材料的理念，對(duì)于毒性、安全性、機(jī)械強(qiáng)度、降解性、成骨性、可塑性等性能的把控，是滿足機(jī)體不同部位骨修復(fù)與骨移植的必要條件。雙相離子摻雜HA通過(guò)制備技術(shù)優(yōu)化和應(yīng)用效果改善，來(lái)適應(yīng)天然骨性能和臨床的要求。

Cao等[71]通過(guò)脈沖激光沉積技術(shù)在金屬鈦植入物表面制備Mg-F-HA涂層。模擬體液浸泡7 d后涂層內(nèi)部結(jié)構(gòu)為類似于松質(zhì)骨的有序線性結(jié)構(gòu)，浸泡14 d后，涂層完全被新形成的磷灰石層覆蓋，表面光滑，干燥過(guò)程中應(yīng)力釋放出現(xiàn)少量裂痕，Mg-F-HA涂層可以長(zhǎng)期保持良好的生物相容性與生物活性，可以在一定程度上調(diào)節(jié)生物降解速率和促進(jìn)細(xì)胞增殖，但涂層裂痕會(huì)使涂層與基體之間存在較大程度的應(yīng)力隱患（見圖6）。

Veerla等[72]采用共沉淀法制備了Ag-Fe-HA納米顆粒，研究發(fā)現(xiàn)控制濃度變化會(huì)使樣品形貌顯現(xiàn)為球形、棒狀和片狀，Ag-Fe-HA樣品具有超順磁性，將納米顆粒分別在普通細(xì)胞（HEK-293）培養(yǎng)皿和癌細(xì)胞（HeLa）培養(yǎng)皿上進(jìn)行培養(yǎng)（見圖7），發(fā)現(xiàn)Ag-Fe-HA的存在幾乎對(duì)細(xì)胞沒(méi)有影響，而癌細(xì)胞長(zhǎng)度明顯變長(zhǎng)，在50Ag50Fe-HA的存在下HeLa細(xì)胞的細(xì)胞膜似乎被破壞，細(xì)胞發(fā)生了劇烈變化如圖8b4，表明Ag-Fe-HA納米顆粒能夠有效靶向殺傷癌細(xì)胞，且對(duì)正常細(xì)胞幾乎無(wú)毒副作用。但是此研究中銀離子與亞鐵離子的實(shí)驗(yàn)組尚未確定Ag+和Fe2+的最佳組合濃度，可以在后續(xù)研究中對(duì)其進(jìn)行深入。

Seyed等[73]采用溶膠凝膠法制備了一種原位硅包覆硅酸根與碳酸根摻雜的HA納米粉體（Si-S- C-HA）。通過(guò)表征發(fā)現(xiàn)非晶態(tài)SiO2包覆層的存在促進(jìn)HA在生理鹽水中離子的釋放，使S-C-HA納米顆粒懸浮在溶液中且?guī)ж?fù)電荷，說(shuō)明非晶態(tài)SiO2層可以加速S-C-HA的生物礦化與改善細(xì)胞附著，但是正是由于表面帶負(fù)電荷會(huì)吸引樣品中的陽(yáng)離子，這樣會(huì)不會(huì)影響樣品中HA結(jié)構(gòu)和性能的變化有待研究。

Abbas等[74]采用機(jī)械化學(xué)合成方法制備了HA- Cl-F，隨著陰離子的雙重取代OH?，樣品的晶粒尺寸、結(jié)晶度和單位細(xì)胞體積呈非線性增大，晶格應(yīng)變逐漸減小，由于粉末的比表面積大和范德華力相互作用，研磨后的樣品具有較高的團(tuán)聚傾向，納米粒子呈現(xiàn)為多邊形和球形組成的簇狀結(jié)構(gòu)，而在高溫煅燒后顆粒逐漸呈等軸狀，在退火過(guò)程中，由于殘余彈性應(yīng)變的大幅度減小，導(dǎo)致晶粒長(zhǎng)大；驚奇的是TEM觀察得到的晶粒尺寸范圍類似于天然骨的20～40 nm范圍[75]（見圖8）。而且發(fā)現(xiàn)樣品在堿性、酸性和中性條件下zeta電位均為負(fù)，負(fù)zeta電位的存在在一定程度上有利于骨整合、磷灰石成核和骨再生。

圖6 SBF溶液浸泡7、14 d后Mg-F-HA涂層微觀結(jié)構(gòu)[71]

圖7 HEK-293、HeLa與納米顆粒培養(yǎng)24 h的高倍（100倍）相位差顯微鏡圖像（a1、b1表示細(xì)胞本身，a2、b2表示HA，a3、b3表示25Ag25Fe-HA，a4、b4表示50Ag50Fe-HA）[72]

Yong等[76]通過(guò)電沉積與陽(yáng)極氧化在利用二氧化鈦納米管(TN)改性的金屬Ti表面上沉積了一種新型的摻銀羥基磷灰石/硅酸鈣（AgHA/CS）層，此涂層實(shí)際上存在的離子交換形式是Ag+和SiO32?與HA中離子進(jìn)行替換，即是另一種意義上的Ag-Si-HA涂層，AgHA/CS涂層表面形貌呈現(xiàn)多孔網(wǎng)狀結(jié)構(gòu)，具有這樣的網(wǎng)絡(luò)結(jié)構(gòu)膜適合于關(guān)節(jié)和牙齒的修復(fù)[77]（見圖9），與純HA涂層相比，該涂層具有優(yōu)異的耐腐蝕性，在對(duì)S.aureus的抑制實(shí)驗(yàn)中體現(xiàn)出較強(qiáng)的抗菌作用，除此之外，Ag-Si-HA涂層還有利于成骨細(xì)胞的附著、增殖與分化。但這樣的結(jié)構(gòu)是否存在較大程度的應(yīng)力缺陷未能體現(xiàn)。電沉積的HA層是均勻的，形態(tài)顯現(xiàn)為花簇或針狀晶體，表面形貌的變化可能是由于Ag+的取代CS（殼聚糖）在HA中的結(jié)合。盡管復(fù)合涂層中的多孔結(jié)構(gòu)可以降低其機(jī)械性能，但它通常有利于成骨細(xì)胞向陶瓷復(fù)合物中的生長(zhǎng)，從而增加骨整合性，這說(shuō)明在多孔網(wǎng)狀結(jié)構(gòu)存在的情況下材料依然可以保持良好的機(jī)械性能。這是否說(shuō)明復(fù)合涂層與基體之間存在著某種界面效應(yīng)影響了涂層與基體的性能？

圖8 機(jī)械研磨60 min的樣品常溫和煅燒后的形貌SEM圖與樣品A1、A2和A3的TEM圖譜[74]

圖9 AgHA/CS涂層表面形貌（a—c），HA涂層表面（d，e），AgHA/CS涂層厚度的橫截面圖像（f）[76]

M. K等[78]通過(guò)脈沖激光沉積法在氧化鋁表面制備了金和碳酸根摻雜的羥基磷灰石（Au-C-HA)涂層。研究發(fā)現(xiàn)，HA粒子呈現(xiàn)為250～450 nm的球狀結(jié)構(gòu)。隨著Au+的增加，剪切模量有明顯變化的趨勢(shì)（先變大后減小），彈性模量逐漸變小但變動(dòng)很小，而顯微硬度會(huì)變大，變化范圍為31～34 Gpa，說(shuō)明Au+的加入可以在一定程度上改善HA涂層的力學(xué)性能（見表1）。在對(duì)HFB4細(xì)胞系培養(yǎng)的實(shí)驗(yàn)中發(fā)現(xiàn)，Au+的加入增強(qiáng)了支架表面的細(xì)胞粘附性，使細(xì)胞不僅在涂層的表面擴(kuò)散與生長(zhǎng)，同時(shí)在涂層的孔隙結(jié)構(gòu)中也不斷地進(jìn)行著增殖和分化。

Wei等[79]研究了化學(xué)沉淀法制備的Se-Sr-HA結(jié)構(gòu)性能和生物性能，發(fā)現(xiàn)SeO32?和Sr2+的共同加入得到了純羥基磷灰石相、降低了Se-Sr-HA的結(jié)晶度、減小了晶粒尺寸，Sr2+的加入影響了樣品的熱穩(wěn)定性；細(xì)胞培養(yǎng)實(shí)驗(yàn)顯示，Se-Sr-HA對(duì)小鼠骨髓間充質(zhì)干細(xì)胞（mBMSCs）無(wú)毒副作用，而其對(duì)人成骨肉瘤細(xì)胞（MG63）有明顯的抑制作用，并發(fā)現(xiàn)Sr2+對(duì)MG63無(wú)影響，真正抑制它的是SeO32?，而Sr2+卻可以促進(jìn)SeO32?的釋放，間接的對(duì)MG63起到了雙重抑制作用，所以Se-Sr-HA有望成為骨癌患者的治療及修復(fù)的雙功能材料。Sr2+是否對(duì)其他離子的釋放均有促進(jìn)作用，這將是后續(xù)研究中較為重要的方向。

表1 各個(gè)涂層的剪切模量（）、體積模量（）、楊氏模量（）和顯微硬度（）的變化[78]

Tab.1 Changes in shear modulus (G), bulk modulus (K), Young's modulus (E) and microhardness (H) of each coating[78]

綜上所述，雙相離子摻雜的羥基磷灰石（X-Y- HA，X和Y表示未知離子）可以在多個(gè)角度影響HA性能，X-Y-HA根據(jù)臨床的實(shí)際需要可以應(yīng)用到植入物表面涂層、藥物緩釋、骨修復(fù)、牙齒美容和癌癥治療等方面，雖然與天然骨材料仍然有一定程度的差距，但雙相離子摻雜在醫(yī)學(xué)和科研領(lǐng)域必定會(huì)有深遠(yuǎn)的應(yīng)用前景和發(fā)展前景。

3 多相離子摻雜羥基磷灰石的研究與展望

單相和雙相離子在結(jié)構(gòu)性能、力學(xué)性能、抗菌性能和成骨性能等多個(gè)方面體現(xiàn)了離子摻雜對(duì)HA影響，然而多相離子摻雜可以站在仿生的角度改性HA，多個(gè)離子同時(shí)存在的HA擁有和天然骨磷灰石更加接近的結(jié)構(gòu)與性能，將可能是未來(lái)骨修復(fù)領(lǐng)域研究與應(yīng)用的重點(diǎn)。在雙相離子摻雜HA中Sr-F-HA在一定條件下可以促進(jìn)成骨細(xì)胞的生長(zhǎng)、增殖和分化，那么在其基礎(chǔ)上多一相或者（≥2）相是否依然存在這樣的性能甚至更多的影響呢？

Gao等[80]通過(guò)水熱法合成了Sr2+、F?和SiO44?共摻雜的羥基磷灰石（Sr-F-Si-HA）。研究發(fā)現(xiàn)制備產(chǎn)物為純HA且結(jié)晶度優(yōu)于HA，在對(duì)MG63細(xì)胞進(jìn)行培養(yǎng)過(guò)程中，發(fā)現(xiàn)其促進(jìn)MG63的粘附和增殖的能力強(qiáng)于HA，說(shuō)明Sr2+、F?和SiO44?的加入確實(shí)增加了HA的骨傳導(dǎo)性。然而前面說(shuō)過(guò)SiO44?在單獨(dú)摻雜羥基磷灰石時(shí)還會(huì)增加HA的抗斷裂韌性與彎曲強(qiáng)度，今后可以對(duì)Sr-F-Si-HA的機(jī)械性能進(jìn)行進(jìn)一步的研究。

Monika等[81]使用脈沖電流在鈦合金材料（Ti6Al4V）表面沉積制備了Ag-Zn-Mg-Sr-HA（m-HA）涂層。涂層顯現(xiàn)為和天然骨的結(jié)構(gòu)相似的多孔海綿狀結(jié)構(gòu)（見圖10），經(jīng)計(jì)算產(chǎn)物中Ca/P為1.55，說(shuō)明HA晶體結(jié)構(gòu)被破壞或出現(xiàn)CaP其他雜質(zhì)相，通過(guò)將成骨MG-63細(xì)胞接種到樣品表面的實(shí)驗(yàn)發(fā)現(xiàn)，細(xì)胞活力值明顯高于裸植入物（Ti6Al4V）和HA涂層的鈦合金材料，且活細(xì)胞在涂層表面致密性與黏附度良好，形態(tài)正常且均勻，說(shuō)明m-HA涂層可以促進(jìn)成骨細(xì)胞的生長(zhǎng)發(fā)育。

圖10 m-HA涂層的不同位置的橫斷面形貌圖（a，b）和EDX能譜圖像（c）[81]

Mirna等[82]采用簡(jiǎn)單沉淀法分別制備了Mg- Mn-Sr-HA。發(fā)現(xiàn)Mg2+和Mn5+在摻雜過(guò)程中很難進(jìn)入HA晶格中，即使有進(jìn)入，量也是相對(duì)較少的，而Sr2+很容易加入HA晶格中，并且三者同時(shí)摻雜HA時(shí)MnO43?和Mg2+的摻入量濃度很高，而Sr2+在Mg-Mn-Sr-HA中的摻入量卻明顯低于Sr-HA，這恰恰表明HA的多相離子共摻雜是一個(gè)高度復(fù)雜的過(guò)程，所以在多相離子摻雜HA的研究過(guò)程中對(duì)其摻雜結(jié)構(gòu)變化與機(jī)理的分析是十分必要的，有利于更多相離子摻雜HA在類骨仿生骨修復(fù)領(lǐng)域的研究。然而，多相離子的共同摻雜是否存在著離子之間的相互作用致使性能的改變，Sr2+的促進(jìn)作用是否時(shí)刻存在，并且是否存在先后順序，其他金屬陽(yáng)離子是否也存在這種作用，或者同時(shí)摻入單相甚至多相陰離子結(jié)果又如何呢？

Vu等[83]采用等離子體噴涂方法在金屬鈦合金材料表面制備HA涂層和ZnSiAg-HA涂層。研究發(fā)現(xiàn)涂層與基材之間有很強(qiáng)的結(jié)合且在基材上保持完整，在磷酸鹽緩沖液（PBS）和pH為5的醋酸緩沖液（ABS）中Ag+總釋放量分別為0.000 171%、0.001 870%，這是由于酸性條件下增加了HA的降解速率。摻雜涂層在中性環(huán)境下同HA涂層均可長(zhǎng)期存在，在酸性條件下14 d后HA涂層完全消失，而ZnSiAg-HA涂層仍有部分存在，說(shuō)明ZnSiAg-HA涂層具有更好的結(jié)晶度；通過(guò)大鼠股骨遠(yuǎn)端模型分析基材本身、HA涂層和ZnSiAg-HA涂層假體的早期骨整合。到第5周，摻雜涂層顯示68%的總骨形成，而HA涂層只有55%，ZnSiAg-HA涂層能產(chǎn)生32%的骨礦化，而HA涂層僅能產(chǎn)生11%的骨礦化，說(shuō)明ZnSiAg-HA涂層的骨結(jié)合能力相對(duì)較強(qiáng)。該系統(tǒng)可應(yīng)用于矯形、牙齒置換以及翻修手術(shù)，以促進(jìn)早期種植體骨整合，縮短愈合時(shí)間。

多相離子摻雜HA的研究并不豐富，原因可能是多離子取代HA的過(guò)程與結(jié)構(gòu)變化太為復(fù)雜，但是由于天然骨磷灰石中多種微量離子的存在，那么人工合成的多相離子摻雜HA的研究就必須深入。

4 總結(jié)

本研究總結(jié)了單相、雙相及多相離子摻雜羥基磷灰石對(duì)HA的性能的影響，但是和天然骨磷灰石相比仍然存在差距，多相離子摻雜HA的研究還不夠深入，對(duì)于天然骨磷灰石的多種離子成分的存在，我認(rèn)為后續(xù)的研究可以根據(jù)天然骨磷灰石中各離子所占比例進(jìn)行摻雜制備類骨磷灰石材料，還可以通過(guò)控制大多數(shù)離子的占比，進(jìn)行單相離子或多相離子比例的動(dòng)態(tài)浮動(dòng)改變HA的晶粒尺寸、拓?fù)浣Y(jié)構(gòu)、化學(xué)成分、結(jié)晶度和表面電荷，從而達(dá)到深層次改性的效果，而且在此基礎(chǔ)上改變制備方法和反應(yīng)條件或許可以更加接近仿生的目的?？傊?，在未來(lái)骨的再生和修復(fù)臨床中，納米羥基磷灰石材料將會(huì)起到關(guān)鍵性的作用，所以離子摻雜改性HA達(dá)到符合臨床要求的研究更加需要進(jìn)一步開展。

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Hydroxyapatite Nanomaterials Doped with Single-phase,Dual-phase and Multiphase Ions

1a1b,2,1b,1b

(1. a. College of Science, b. College of Materials Science and Engineering, Liaoning Technical University, Liaoning Fuxin 123000, China; 2. Ganli Pharmaceutical Co., Ltd., Beijing 101102, China)

Hydroxyapatite is an important part of natural bone tissue composition and has always been the focus of attention and research in the field of biomedicine. The apatite in the natural bone composition is a kind of hydroxyapatite combined with a variety of ions, which maintains the normal growth and development of life systems. With the systematic research on single-phase ion doping, the preparation and performance of dual-phase and multi-phase doped hydroxyapatite are being continuously expanded. The preparation and performance of phase and heterogeneous ion-doped hydroxyapatite are systematically elaborated and summarized.

This study expounds the crystal structure of hydroxyapatite, describes the advantages and performance advantages of synthetic hydroxyapatite itself, hydroxyapatite with good biological properties as a coating has been widely used in experiments to replace bone, but Some performance deficiencies limit its application. The study outlines the researchers' research on the effects of different ion doping or different forms of doping on the properties of hydroxyapatite, including biocompatibility, biological activity, suitable mechanical strength, excellent bone formation performance and corrosion resistance performance. At the same time, the different substitution sites of anion and cation doped hydroxyapatite are summarized.

On this basis, starting from the preparation and performance research of single-phase ion-doped hydroxyapatite, the performance changes caused by different ion doping and the corresponding mechanism are explained. Prospects and shortcomings. Based on the single-phase ion-doped hydroxyapatite in the past five years, it is necessary to explore the effects of two-phase and multi-phase ion-doped hydroxyapatite on the structural properties, mechanical strength, antibacterial properties, degradability, and osteogenic properties. A certain pavement. At the same time, two-phase and multi-phase ion doping of hydroxyapatite found that the doping ions will promote each other. By doping hydroxyapatite in different phases, it is found that the performance of multi-phase doping is based on the synergistic effect of single-phase or multi-phase doping. In addition, the doping of hydroxyapatite with trace ions can promote the activity of bone cells, promote the growth, proliferation and differentiation of bone cells, and thus play a role in inducing bone formation. However, doping with different ions will produce different properties. The doping of hydroxyapatite with magnesium, iron, zinc, strontium, and fluorine will produce different degrees of antibacterial properties against Escherichia coli or Staphylococcus aureus. Part of the ions doped with hydroxyapatite will increase the mechanical properties of the material and increase the degradation performance.

Through more systematic preparation and performance research of single-phase and dual-phase doped hydroxyapatite, a more effective preparation method has been explored for realizing multiphase doped hydroxyapatite. In recent years, although hydroxyapatite bioceramic materials have been used clinically as implant coatings, sustained-release drug carriers, and bone graft replacement materials, they still face many problems and challenges in their widespread use in clinical practice. Therefore, this article also looks forward to the future development direction of ion-doped hydroxyapatite, paving the way for exploring the preparation method and performance of heterogeneous ion-doped hydroxyapatite, making the preparation closer to natural crystal structure and performance The bionic bone material of apatite is expected to have certain guiding significance in clinical application and development.

TB34

A

1001-3660(2022)10-0143-12

10.16490/j.cnki.issn.1001-3660.2022.10.014

2021–08–03；

2021–11–08

2021-08-03；

2021-11-08

遼寧省教育廳項(xiàng)目（LJ2020JCL033）

Liaoning Provincial Department of Education Project (LJ2020JCL033)

劉瑩（1970—），男，碩士，教授，主要研究方向?yàn)樯锘瘜W(xué)及天然高分子材料。

LIU Ying (1970-), Male, Master, Professor, Research focus: biochemistry and natural polymer materials.

劉瑩, 楊瑞, 劉井來(lái), 等. 單相、雙相及多相離子摻雜的羥基磷灰石研究進(jìn)展[J]. 表面技術(shù), 2022, 51(10): 143-154.

LIU Ying, YANG Rui, LIU Jing-lai, et al. Hydroxyapatite Nanomaterials Doped with Single-phase, Dual-phase and Multiphase Ions[J]. Surface Technology, 2022, 51(10): 143-154.