劉瑋瑋，李攀，李浩，趙一風(fēng)，劉榮臻,2*，李家良

數(shù)字光處理技術(shù)成形β-磷酸三鈣生物陶瓷及其生物學(xué)評(píng)價(jià)

劉瑋瑋1，李攀1，李浩1，趙一風(fēng)1，劉榮臻1,2*，李家良3

（1.西安增材制造國(guó)家研究院有限公司，西安 710117；2.西安交通大學(xué) 材料科學(xué)與工程學(xué)院，西安 710049；3.西安紅會(huì)醫(yī)院，西安 710054）

研究數(shù)字光處理技術(shù)（Digital Light Processing，DLP）打印β-磷酸三鈣（Beta-Tricalcium Phosphaye，β-TCP）生物陶瓷的成形性能與生物學(xué)性能。通過(guò)表面活性劑硬脂酸改性β-TCP粉體，將改性后的β-TCP粉體與丙烯酸類及甲基丙烯酸類樹(shù)脂均勻混合成3D打印漿料，進(jìn)行3D打印性能研究。采用X射線衍射儀（X-Ray Diffraction，XRD）、接觸角測(cè)量?jī)x、數(shù)字式黏度計(jì)表征β-TCP粉體、漿料及3D打印支架性能，并進(jìn)行體外細(xì)胞試驗(yàn)研究β-TCP多孔支架的生物學(xué)性能。粉體XRD結(jié)果顯示，硬脂酸改性β-TCP粉體并未影響原始粉體的物相組成；而表面活性劑硬脂酸降低了樹(shù)脂與粉體表面的接觸角，提高了粉體與樹(shù)脂的親和性。3D打印β-TCP漿料的固含量為48%（體積分?jǐn)?shù)），在常溫下，黏度僅為2.91 Pa·s。支架XRD結(jié)果顯示，3D打印β-TCP多孔支架的主要物質(zhì)仍為β-TCP，僅有部分轉(zhuǎn)化為α-TCP。體外細(xì)胞試驗(yàn)表明，3D打印β-TCP支架表面可黏附大量細(xì)胞，培養(yǎng)7 d后，細(xì)胞延伸至支架孔隙內(nèi)，同時(shí)其溶血性結(jié)果較鈦合金（Ti6Al4V）及聚醚醚酮（PEEK）的優(yōu)異。3D打印β-TCP多孔支架可作為骨替代植入物，為治療臨床骨缺損疾病提供新途徑。

數(shù)字光處理；3D打??；β-磷酸三鈣；生物陶瓷；生物學(xué)性能

β-磷酸三鈣（β-Tricalcium Phosphate，β-TCP）陶瓷屬于生物活性陶瓷材料，一般表現(xiàn)為在植入體內(nèi)后，其表面會(huì)形成強(qiáng)基碳酸根磷灰石層，與人體骨相連，早在20世紀(jì)70年代就被報(bào)道并迅速應(yīng)用于臨床[1-2]。傳統(tǒng)磷酸鈣陶瓷骨植入物的成形方式有干壓成形、濕法成形、擠壓成形、注射成形、直接凝固成形以及造孔方法（粒子浸出法、氣體發(fā)泡法、又?jǐn)D泡沫浸漬法等），這些方法均不能滿足臨床個(gè)性化需求，比如復(fù)雜的外形、精準(zhǔn)的孔隙連通性和孔隙率等[3-4]。

增材制造（又稱3D打?。┘夹g(shù)是通過(guò)計(jì)算機(jī)斷層掃描獲取人體DICOM數(shù)據(jù)，利用逐層疊加方式構(gòu)建三維實(shí)體的方法，可個(gè)性化設(shè)計(jì)。目前陶瓷材料增材制造技術(shù)主要有數(shù)字光處理技術(shù)（Digital Light Processing，DLP）、立體光固化成形（Stereolithography，SLA）、選擇性激光燒結(jié)（Selective Laser Sintering，SLS）、雙光子聚合（Two Photon Polymerization，TPP）[5-6]，其中DLP與SLA具有高速高精度的特點(diǎn)，被廣泛應(yīng)用于陶瓷增材制造[7]。目前大量學(xué)者研究了氧化鋯與氧化鋁等生物陶瓷，但對(duì)光固化成形β-TCP的研究較少。目前應(yīng)用于臨床的骨植入物的材料主要為鈦合金（Ti6Al4V）及聚醚醚酮（PEEK），3D打印的β-TCP骨植入物在臨床中出現(xiàn)較少，有學(xué)者質(zhì)疑3D打印β-TCP骨植入物中殘余的樹(shù)脂成分是否會(huì)在動(dòng)物或人體體內(nèi)產(chǎn)生排異、致敏情況，甚至出現(xiàn)毒性。因此，本文通過(guò)DLP技術(shù)成形β-TCP仿骨小梁結(jié)構(gòu)，研究其成形性能，并與Ti6Al4V及PEEK進(jìn)行生物安全性對(duì)比，探討DLP成形β-TCP骨植入物的生物安全性。

1 實(shí)驗(yàn)

1.1 β-TCP粉體處理及表征

將β-TCP粉體（購(gòu)自邁海新型材料）與一定比例的表面活性劑硬脂酸（購(gòu)自上海麥克林）均勻混合，通過(guò)濕法球磨進(jìn)行改性處理，處理方法如下：將230枚氧化鋯磨球（5枚12 mm、10枚8 mm、35枚6 mm、180枚4 mm）、60 g粉體、1%（質(zhì)量分?jǐn)?shù)）硬脂酸和50 mL無(wú)水乙醇裝入球磨罐中，轉(zhuǎn)速為300 r/min，球磨5 h，將β-TCP與硬脂酸乙醇溶液在70 ℃下烘干，多次稱量至恒重，研磨后，過(guò)100目篩，獲得改性后β-TCP粉體（Modified-β-TCP，M-β-TCP）。

通過(guò)X射線衍射儀（X-Ray Diffraction，XRD，型號(hào)為帕納科Empyream）檢測(cè)改性前后β-TCP粉體的物相組成，檢測(cè)參數(shù)如下：掃描范圍為10°～60°、掃描速度為0.2（°）/s。通過(guò)接觸角測(cè)量?jī)x（型號(hào)為中儀科信JC2000DM），分別將5 g改性前后的β-TCP粉體制成片狀，檢測(cè)改性前后β-TCP的樹(shù)脂接觸角與水接觸角，每個(gè)樣品任取6個(gè)測(cè)試點(diǎn)進(jìn)行測(cè)試。

1.2 3D打印M-β-TCP支架性能檢測(cè)

采用丙烯酸與甲基丙烯酸樹(shù)脂（購(gòu)自上海光易材料有限公司）作為樹(shù)脂配方，如表1所示。選擇819與651作為光引發(fā)劑、BYK110作為分散劑[8]，加入一定量的M-β-TCP粉體，通過(guò)均質(zhì)機(jī)以1 800 r/min速度攪拌2 min后配制成M-β-TCP漿料。利用自研的下沉式DLP陶瓷打印機(jī)（型號(hào)為MagicBook F2），在激光電流百分比為45%、曝光時(shí)間為5 s條件下打印M-β-TCP多孔骨植入物（軟件設(shè)計(jì)仿骨小梁結(jié)構(gòu)）。

表1 3D打印M-β-TCP漿料樹(shù)脂配方

通過(guò)數(shù)字式黏度計(jì)（型號(hào)為NDJ-8S）表征M-β- TCP漿料的黏度，每個(gè)樣品取6個(gè)黏度數(shù)據(jù)。通過(guò)X射線衍射儀（型號(hào)同1.1）檢測(cè)M-β-TCP支架的物相組成，檢測(cè)參數(shù)同1.1。

1.3 細(xì)胞學(xué)評(píng)價(jià)

通過(guò)3D打印技術(shù)制備仿骨小梁結(jié)構(gòu)的Ti6Al4V支架與PEEK支架，結(jié)構(gòu)設(shè)計(jì)同1.2。利用熒光顯微鏡與SEM觀察M-β-TCP支架的細(xì)胞黏附性及鋪展性。按照ISO 10993-4: 2002標(biāo)準(zhǔn)[9]，分別將具有仿骨小梁結(jié)構(gòu)的3D打印M-β-TCP、Ti6Al4V、PEEK支架與小白鼠血紅細(xì)胞在體外接觸，判斷所致紅細(xì)胞溶解和血紅蛋白游離程度，對(duì)比研究M-β-TCP、Ti6Al4V與PEEK支架的細(xì)胞溶血毒性、細(xì)胞增殖性等，并對(duì)3D打印β-TCP、Ti6Al4V與PEEK支架的細(xì)胞堿性磷酸酶（Alkaline Phosphatase，ALP）活性表達(dá)進(jìn)行初步研究，評(píng)價(jià)3種材料誘導(dǎo)組織再生的意義。

2 結(jié)果與分析

2.1 3D打印β-TCP粉體及漿料性能

β-TCP改性前后粉末的XRD圖譜如圖1a所示?？梢?jiàn)，β-TCP粉末中主極大衍射峰在2=31.023°附近，次主極大衍射峰在2=34.335°附近，第三主極大衍射峰在2=27.777°附近，與標(biāo)準(zhǔn)PDF卡片010702065#（β-TCP）的主要衍射峰位置一致。改性后β-TCP（M-β-TCP）粉末的衍射鋒位置未發(fā)生明顯改變，說(shuō)明改性處理不會(huì)改變?cè)挤勰┑奈锵嘟M成。經(jīng)Highscore軟件測(cè)算可知，β-TCP的結(jié)晶度為51.71%，M-β-TCP的結(jié)晶度為39.15%。經(jīng)過(guò)球磨后，β-TCP的物相組成未改變，結(jié)晶度下降，這主要是由于球磨提供了能量，導(dǎo)致β-TCP的結(jié)晶度下降，同時(shí)硬脂酸的加入也使粉末出現(xiàn)非晶化。改性前后β-TCP對(duì)水與樹(shù)脂的親和性如圖1b所示?？梢?jiàn)，與改性前的β-TCP相比，改性后的M-β-TCP顯示出超疏水性，且兩者具有極顯著性差異，對(duì)水的接觸角由18°提升到140°以上；改性后M-β-TCP的樹(shù)脂接觸角較改性前的低（由53°降低至37°），出現(xiàn)顯著性差異。由改性后M-β-TCP粉末配制的3D打印漿料（固含量為48%，體積分?jǐn)?shù)）在室溫下的黏度為2.91 Pa·s，且漿料的黏度隨溫度的升高而降低（見(jiàn)圖2）。由于硬脂酸具有大量疏水基團(tuán)[10]，M-β-TCP粉末表面包覆硬脂酸，使其表面轉(zhuǎn)變?yōu)槭杷?，且硬脂酸與樹(shù)脂具有強(qiáng)親和性，因此M-β-TCP表現(xiàn)出強(qiáng)疏水性、強(qiáng)樹(shù)脂親和性，最終獲得了高固含量低黏度的3D打印漿料。

DLP成形β-TCP的核心技術(shù)是漿料的制備，漿料需既能滿足高固含量又能滿足低黏度（分散越均勻，在同一黏度下的固含量越高），其中粉體在樹(shù)脂中的分散性會(huì)影響漿料的黏度與固含量[11-12]。粉體在樹(shù)脂中能否形成分散均勻穩(wěn)定的體系取決于粉體與粉體間的作用力，當(dāng)粉體間的斥力大于引力時(shí)，體系穩(wěn)定，當(dāng)斥力小于引力時(shí)，粉體易產(chǎn)生團(tuán)聚[13-15]。四川大學(xué)生物醫(yī)學(xué)工程學(xué)院/國(guó)家生物醫(yī)學(xué)材料工程技術(shù)研究中心張興棟院士團(tuán)隊(duì)與四川大學(xué)華西骨科屠重棋教授團(tuán)隊(duì)基于DLP技術(shù)制備了磷酸鈣漿料，其固含量為50%（質(zhì)量分?jǐn)?shù)），黏度約為3 Pa·s，與本研究相比，黏度接近，但固含量較低[16]。上海交通大學(xué)Li等[17]配制了β-TCP與生物玻璃（58S BG）光固化漿料，固含量為34%（體積分?jǐn)?shù)），黏度為85.92 Pa·s，與本研究相比，固含量更低且黏度更高。華中科技大學(xué)吳甲民團(tuán)隊(duì)配制了雙相磷酸鈣（Diphase Calcium Phosphate，BCP）與生物玻璃（45S5 BG）光固化漿料，固含量?jī)H為40%（體積分?jǐn)?shù)）[18]。

2.2 3D打印M-β-TCP支架及性能檢測(cè)

通過(guò)DLP打印的M-β-TCP支架如圖3a所示，3D打印M-β-TCP生物陶瓷件燒結(jié)后的XRD圖譜如圖3b所示。對(duì)比β-TCP標(biāo)準(zhǔn)PDF卡片（卡片號(hào)010702065#）的主要衍射峰位置可知，M-β-TCP支架的主要衍射峰位置與β-TCP標(biāo)準(zhǔn)PDF卡片的位置基本相同，同時(shí)觀察到α-TCP物質(zhì)的衍射峰（卡片號(hào)090348#），說(shuō)明經(jīng)燒結(jié)后，M-β-TCP支架的主要物質(zhì)為β-TCP，有部分轉(zhuǎn)化為高溫α-TCP。

圖1 改性前后β-TCP粉末的XRD圖譜（a）及粉末分別對(duì)水、樹(shù)脂的接觸角（b）

圖2 不同溫度下3D打印M-β-TCP漿料的黏度

2.3 細(xì)胞學(xué)評(píng)價(jià)

3D打印仿骨小梁結(jié)構(gòu)的β-TCP支架與MC3T3- E1細(xì)胞共培養(yǎng)7 d后支架表面與內(nèi)部的熒光顯微照片如圖4所示?？梢?jiàn)，活細(xì)胞被Calcein-AM染料染色，支架表面與內(nèi)部均有一定數(shù)量的細(xì)胞黏附，鋪展?fàn)顟B(tài)良好，細(xì)胞偽足明顯（圓圈所示）。3D打印仿骨小梁結(jié)構(gòu)的M-β-TCP支架與MC3T3-E1細(xì)胞共培養(yǎng)7 d后的SEM圖如圖5所示。SEM顯示，β-TCP支架表面細(xì)胞呈梭形，偽足與支架表面緊密黏附（箭頭所示），由圖5b可以看到，細(xì)胞間偽足互相連接。與熒光顯微照片現(xiàn)象結(jié)合可知，通過(guò)3D打印構(gòu)建的M-β-TCP支架表現(xiàn)出良好的細(xì)胞黏附與細(xì)胞相容性。

溶血性試驗(yàn)主要是觀察樣品是否會(huì)引起溶血和紅細(xì)胞凝聚等反應(yīng)，某些材料因含有雜質(zhì)成分，注入血管后易產(chǎn)生紅細(xì)胞凝聚，引起血液循環(huán)功能障礙等一系列不良反應(yīng)，另外，因材料成分復(fù)雜，也會(huì)存在因免疫反應(yīng)而引起免疫性溶血現(xiàn)象，溶血可導(dǎo)致某些器官形成血栓，進(jìn)而受損[19-20]。因此，凡可能引起免疫性溶血或非免疫性溶血反應(yīng)的材料均應(yīng)進(jìn)行溶血性試驗(yàn)，通常材料的溶血率越低，表明該材料的安全性越高[21]。3D打印M-β-TCP、Ti6Al4V與PEEK支架的細(xì)胞溶血反應(yīng)前后的現(xiàn)象及溶血毒性反應(yīng)數(shù)據(jù)結(jié)果如圖6所示。可見(jiàn)，M-β-TCP、Ti6Al4V與PEEK材料均未出現(xiàn)明顯的溶血毒性。M-β-TCP對(duì)血細(xì)胞的溶血率為（0.73±0.024）%，與Ti6Al4V（1.24%±0.030%）和PEEK（0.93%±0.012%）有顯著性差異，因此，3D打印M-β-TCP不會(huì)引起血紅細(xì)胞凝聚進(jìn)而產(chǎn)生血液循環(huán)功能障礙的現(xiàn)象。

圖3 3D打印M-β-TCP生坯件（a）及燒結(jié)后的XRD圖譜（b）

圖4 3D打印仿骨小梁結(jié)構(gòu)的M-β-TCP支架與小鼠顱骨前成骨細(xì)胞（MC3T3-E1）細(xì)胞共培養(yǎng)7 d后支架表面（a）與內(nèi)部（b）的熒光顯微照片

圖6 3D打印M-β-TCP、Ti6Al4V與PEEK支架對(duì)兔血紅細(xì)胞的溶血反應(yīng)與陰陽(yáng)性對(duì)照?qǐng)D及溶血毒性反應(yīng)數(shù)據(jù)結(jié)果

ALP是早期成骨分化的標(biāo)志，通過(guò)檢測(cè)ALP活性，可反映不同材料對(duì)細(xì)胞成骨分化的影響[22-23]。3D打印M-β-TCP、Ti6Al4V、PEEK支架與小鼠顱骨前成骨細(xì)胞（MC3T3-E1）共培養(yǎng)的細(xì)胞增殖情況與堿性磷酸酶（ALP）活性如圖7所示。細(xì)胞增殖結(jié)果顯示，與PEEK和Ti6Al4V支架相比，M-β-TCP的細(xì)胞OD值存在顯著性差異，說(shuō)明M-β-TCP較Ti6Al4V和PEEK的細(xì)胞相容性更佳，也更有利于促進(jìn)細(xì)胞增殖。ALP活性結(jié)果顯示，在2周時(shí)3種材料的ALP分泌均呈現(xiàn)高值，而共培養(yǎng)3周時(shí)ALP活性表達(dá)相較于2周時(shí)的有所降低，這可能是因?yàn)樵诔晒浅跗冢?種材料均可加速促進(jìn)成骨細(xì)胞分化，而后期逐漸減緩。在共培養(yǎng)2周時(shí)，M-β-TCP的ALP活性表達(dá)與PEEK出現(xiàn)顯著性差異，其余組均無(wú)顯著性差異，表明3種材料在短期內(nèi)的成骨性相似。β-TCP材料的主要成分為鈣和磷，與人體主要無(wú)機(jī)成分相同[24]，在臨床上作為骨植入物更加適用，而Ti6Al4V的彈性模量高于皮質(zhì)骨的，易造成周圍骨組織吸收，骨強(qiáng)度降低，產(chǎn)生應(yīng)力遮擋[25]，PEEK為生物惰性材料，植入物周圍易形成纖維組織包裹且骨整合能力較弱[26]。綜上所述，β-TCP材料較Ti6Al4V、PEEK更適宜作為骨植入替代物。

圖7 3D打印M-β-TCP、Ti6Al4V與PEEK支架與小鼠顱骨前成骨細(xì)胞（MC3T3-E1）共培養(yǎng)的細(xì)胞增殖情況（a）與堿性磷酸酶（ALP）活性（b）

3 結(jié)論

1）通過(guò)硬脂酸改性β-TCP粉體不會(huì)影響其原粉體的物相組成，僅表現(xiàn)為結(jié)晶度下降，β-TCP的結(jié)晶度為51.71%，M-β-TCP的結(jié)晶度為39.15%。球磨使表面活性劑硬脂酸均勻包裹于β-TCP粉體表面，從而增加了β-TCP粉體與樹(shù)脂的親和性，獲得高固含量（48%，體積分?jǐn)?shù)）低黏度（常溫下為2.91 Pa·s）的3D打印漿料。

2）經(jīng)過(guò)脫脂燒結(jié)后，通過(guò)DLP成形的M-β-TCP支架的物相組成主要為β-TCP，僅有部分轉(zhuǎn)換為α-TCP。

3）體外細(xì)胞試驗(yàn)表明，經(jīng)燒結(jié)后，DLP成形M-β-TCP支架無(wú)細(xì)胞毒性，且與目前臨床常用植入材料Ti6Al4V與PEEK對(duì)比得出，M-β-TCP的細(xì)胞溶血性及細(xì)胞增殖情況均優(yōu)于Ti6Al4V與PEEK。

本研究通過(guò)改性β-TCP粉末，配制出高固低黏的3D打印漿料，且進(jìn)行了體外細(xì)胞試驗(yàn)驗(yàn)證，為增材制造β-TCP骨支架在臨床上的應(yīng)用提供了基礎(chǔ)理論。

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Fabrication of β-tricalcium Phosphate Bioceramics by Digital Light Processing Technique and Its Biological Evaluation

LIU Wei-wei1, LI Pan1, LI Hao1, ZHAO Yi-feng1, LIU Rong-zhen1,2*, LI Jia-liang3

(1. Xi’an Additive Manufacturing National Institute Co., Ltd., Xi’an 710117, China; 2. School of Materials Science and Engineering, Xi’an Jiaotong University, Xi’an 710049, China; 3. Xi’an Honghui Hospital, Xi’an 710054, China)

The work aims to study the formability and biological properties of β-Tricalcium Phosphate (β-TCP) bioceramics printed by digital light processing (DLP) technique. β-TCP powder modified by surfactant stearic acid was evenly mixed with acrylic resins and methacrylic resin to form 3D printed slurry, and then the 3D printed process was verified. An X-ray diffractometer (XRD), a contact Angle measuring instrument, and a digital viscometer were used to characterize the properties of β-TCP powder, slurry and 3D printed scaffolds. The biological properties of β-TCP porous scaffolds were studied by cell and animal experiments. The powder XRD results showed that the modification of β-TCP powder did not affect the phase composition of the powder. The surfactant stearic acid reduced the contact angle between the resin and the powder surface, and improved the affinity between the powder and the resin. The solid content of 3D printed β-TCP slurry was 48vol.% and the viscosity was only 2.91 Pa·s at room temperature. The scaffold XRD results showed that the main substance of sintered scaffold was β-TCP, and part of it was transformed into α-TCP. In vitro cell experiments showed that the surface of 3D printed β-TCP scaffolds could adhere to a large number of cells. After 7 days of culture, the cells extended into the pores of the scaffold. And the hemolytic results were better than those of Ti6Al4V and PEEK. 3D printed β-TCP porous scaffolds can be used as bone replacement implants, providing a new way to treat clinical bone defect diseases.

digital light processing; 3D printed; β-tricalcium phosphate; bioceramics; biological properties

10.3969/j.issn.1674-6457.2023.011.008

TH145.9；TB321

A

1674-6457(2023)011-0069-07

2023-10-07

2023-10-07

陜西省重點(diǎn)研發(fā)計(jì)劃重點(diǎn)產(chǎn)業(yè)創(chuàng)新鏈項(xiàng)目（2017KTZD6-01）；陜西省科技統(tǒng)籌創(chuàng)新工程計(jì)劃（2016KTZDGY4-06）

Shaanxi Province Key R&D Programme Key Industrial Innovation Chain Project (2017KTZD6-01); Shaanxi Province Science and Technology Coordination and Innovation Engineering Programme (2016KTZDGY4-06)

劉瑋瑋, 李攀, 李浩, 等. 數(shù)字光處理技術(shù)成形β-磷酸三鈣生物陶瓷及其生物學(xué)評(píng)價(jià)[J]. 精密成形工程, 2023, 15(11): 69-75.

LIU Wei-wei, LI Pan, LI Hao, et al. Fabrication of β-tricalcium Phosphate Bioceramics by Digital Light Processing Technique and Its Biological Evaluation[J]. Journal of Netshape Forming Engineering, 2023, 15(11): 69-75.

通信作者（Corresponding author）

責(zé)任編輯：蔣紅晨