沈?qū)W霖，朱光明，楊鵬飛

(西北工業(yè)大學(xué) 應(yīng)用化學(xué)系，西安 710129)

生物醫(yī)用形狀記憶高分子材料

沈?qū)W霖，朱光明，楊鵬飛

(西北工業(yè)大學(xué) 應(yīng)用化學(xué)系，西安 710129)

形狀記憶聚合物作為一種智能材料，已經(jīng)在生物醫(yī)用領(lǐng)域顯示出了巨大的應(yīng)用前景。基于形狀記憶聚合物材料的原理，組成和結(jié)構(gòu)可以設(shè)計兼具生物降解性、生物相容性等多種功能的新型智能材料。本文綜述了三種典型的生物降解性形狀記憶聚合物材料(聚乳酸、聚己內(nèi)酯、聚氨酯)的發(fā)展，從結(jié)構(gòu)上對三種形狀記憶聚合物進(jìn)行了分類討論，詳細(xì)分析了不同種類聚合物形狀記憶的機理、形狀變化的固定率和回復(fù)率、回復(fù)速率等，并介紹了一些形狀記憶聚合物材料在生物醫(yī)學(xué)中的應(yīng)用。最后對醫(yī)用形狀記憶聚合物未來發(fā)展進(jìn)行了展望：雙程形狀記憶聚合物及體溫轉(zhuǎn)變形狀記憶材料將會受到研究者的重點關(guān)注。

生物醫(yī)用；形狀記憶聚合物；聚乳酸；聚己內(nèi)酯；聚氨酯

形狀記憶聚合物(shape memory polymers)是一類具有刺激-響應(yīng)的新型智能高分子材料，其能感知外界環(huán)境變化，并對外界刺激做出響應(yīng)，從而自發(fā)調(diào)節(jié)自身狀態(tài)參數(shù)恢復(fù)到預(yù)先設(shè)計的狀態(tài)[1]。兼具生物相容性和生物降解性的SMPs已經(jīng)在微創(chuàng)外科手術(shù)[2,3]、血管支架[4,5]、骨組織的固定[6,7]、可控藥物緩釋[8,9]、血栓移除[10]中得到了應(yīng)用。本文詳細(xì)討論了聚乳酸基、聚己內(nèi)酯基和聚氨酯基三種最常見的生物降解形狀記憶聚合物的研究狀況。

1 聚乳酸基形狀記憶聚合物

聚乳酸類材料是一種典型的生物醫(yī)用材料，具有良好的生物相容性和生物降解性，小分子降解產(chǎn)物能通過體內(nèi)代謝排出體外[11]。按照形狀記憶聚乳酸的分子結(jié)構(gòu)可將其分為聚乳酸共聚物，聚乳酸共混物和聚乳酸基復(fù)合材料三類。

純的聚乳酸材料脆而硬，親水性差，強度高但其韌性較差，極大地限制了其在生物醫(yī)學(xué)領(lǐng)域中的應(yīng)用[12]。在聚乳酸基體中引入第二單體形成聚乳酸基共聚物，能顯著地改善其性能。通過調(diào)節(jié)PLA與其他單體的比例，可以得到韌性好、降解速率可調(diào)，力學(xué)性能優(yōu)異的共聚形狀記憶聚乳酸材料[13,14]。聚己內(nèi)酯(PCL)[15-17]和聚乙醇酸(PGA)[18]是聚乳酸基形狀記憶聚合物常用共聚單元，此外對二氧環(huán)酮[19,20]，乙交酯[19]與PLA的共聚物也能表現(xiàn)出形狀記憶性能。

Peponi等[15]用聚己內(nèi)酯和聚乳酸共聚，合成了一種PLLA-PCL-PLLA的三嵌段共聚物。硬段PLLA作為固定相，軟段PCL作為轉(zhuǎn)變相(switching segment)。三嵌段共聚物的轉(zhuǎn)變溫度(37～40℃)接近于人體溫度。Yu等[21]在此基礎(chǔ)上用PCLA共聚物(組成比DL-LA/ε-PCL為90/10)制備了一種生物降解性的食道支架，這種形狀記憶支架的轉(zhuǎn)變溫度為37℃。在動物體內(nèi)降解測試中，支架能夠保持足夠的抗壓強度，防止食道狹窄。

姜繼森等[18]用開環(huán)聚合的方法合成了一系列組成不同的形狀記憶聚(乳酸-乙醇酸)(PLGA)二元共聚物。乙醇酸含量的增加會降低共聚物的結(jié)晶度，但PLGA記憶形變的能力大大加強，形狀回復(fù)率增大，回復(fù)力經(jīng)歷了先增大后減小的過程。Knight等[22]在PLGA主鏈上引入POSS，PLGA端基不飽和改性后(與丙烯酰氯反應(yīng))在紫外光作用下聚合得到了一種PLGA-POSS端基交聯(lián)網(wǎng)絡(luò)的形狀記憶聚合物。其中，POSS不僅作為起始劑開環(huán)聚合PLGA，結(jié)晶的POSS相還充當(dāng)了固定相。

聚乳酸多元共聚物也能表現(xiàn)出形狀記憶性能，Zini等[3]通過開環(huán)聚合的方法制備了一系列不同組成的乳酸-乙交酯-三亞甲基碳酸酯三元共聚物(LA-GA-TMC)，形狀回復(fù)率超過89%(圖1)。共聚物的形狀轉(zhuǎn)變溫度(玻璃化轉(zhuǎn)變溫度)隨乳酸含量的變化可調(diào)，高乳酸含量的三元共聚物玻璃化轉(zhuǎn)變溫度在人體溫度附近。

1.2 聚乳酸共混物

聚乳酸基SMPs共聚物主要是通過共聚單體化學(xué)鍵合形成高分子網(wǎng)絡(luò)，而聚合物共混物則是通過高分子鏈段互相纏結(jié)形成“互穿聚合物網(wǎng)絡(luò)”結(jié)構(gòu)(IPN)[23,24]?；贗PN結(jié)構(gòu)設(shè)計SMPs，可以大幅提高其玻璃態(tài)模量和橡膠態(tài)模量比值，即提高SMP的形狀固定率和回復(fù)率[25]。聚乳酸基形狀記憶聚合物的共混單元有TPU(熱塑性彈性體)[26-28]，PEG(聚乙二醇)[29]，PAE(聚酰胺彈性體)[30,31]，PU(聚氨酯)[32]等。

圖1 三元共聚物的形狀記憶實驗(回復(fù)過程溫度48℃)[3]Fig.1 Shape memory experiment of terpolymer (the recovery process at 48℃) [3]

Jing研究小組[33-35]系統(tǒng)地研究了PLA/TPU共混物的微觀形貌特征、力學(xué)性能、形狀記憶效應(yīng)以及降解性。Jing等將不同組成的PLA和TPU熔融共混物在雙螺桿擠出機中熱壓成型，室溫下材料經(jīng)過彎曲、壓縮、拉伸等過程變形，當(dāng)溫度超過PLA玻璃化轉(zhuǎn)變溫度(70℃)，材料即可回復(fù)至初始形狀。圖2所示為形變記憶性能的機理，PLA的結(jié)晶區(qū)作為固定相決定材料的初始形狀，可逆相為PLA的無定型部分。

何謂統(tǒng)計量？它是指抽樣統(tǒng)計中觀察頻數(shù)與期望頻率之間可能存在著差異，統(tǒng)計量的基本想法是對每一個差取平方，然后除以期望頻率再取和，就得到一個統(tǒng)計量，該統(tǒng)計量就稱為統(tǒng)計量，即

圖2 PLA/TPU共混物的形狀記憶機理[33]Fig.2 Shape memory mechanism of PLA/TPU blends[33]

Gu等[32]用溶液澆注的手段制備了 PU/PLA-PTMEG共混物，SEM顯示這種共混物具有微相分離結(jié)構(gòu)和兩個不同的玻璃化轉(zhuǎn)變，材料具有三重形狀記憶性能。

1.3 聚乳酸基復(fù)合材料

形狀記憶聚合物的缺陷在于其機械強度低，熱穩(wěn)定性差，回復(fù)力小，循環(huán)記憶效應(yīng)不佳。無機納米粒子與聚乳酸復(fù)合制備形狀記憶有機/無機復(fù)合材料，能使復(fù)合材料的力學(xué)性能、熱穩(wěn)定性能、降解性等得到明顯的改善[36]。

國內(nèi)西南交通大學(xué)周紹兵課題組將聚乳酸與磷酸三鈣(β-TCP)[37]、羥基磷灰石(HA)[38]、微晶纖維素[39]等多種納米填料粒子復(fù)合制備了形狀記憶材料。磷酸鈣鹽類是骨科和牙科治療中常用的生物材料，其骨傳導(dǎo)性好，生物降解性和吸收性強。Zheng等[38]用SEM,DSC,DMA分別表征了PDLLA/HA復(fù)合物的表面形貌、玻璃化轉(zhuǎn)變、動態(tài)力學(xué)性能和形狀記憶性能，形狀回復(fù)率和回復(fù)時間最佳的組成比在2.0～2.5之間。而Du等[40]用原位聚合制備了不同HA含量的HA-g-PDLA接枝納米復(fù)合材料，形狀記憶最優(yōu)組成比為15%。此外作者研究發(fā)現(xiàn)質(zhì)量分?jǐn)?shù)25%的HA-g-PDLA接枝共聚物比HA/PDLA共混物的形狀記憶性能優(yōu)異，不同含量HA的納米復(fù)合材料形狀記憶過程如圖3所示。

無機填料可作為增強材料提高形狀記憶聚合物的性質(zhì)，另一方面，將聚乳酸與磁性納米粒子和導(dǎo)電粒子復(fù)合，得到的材料不僅對溫度具有響應(yīng)，而且在交變磁場和電場中也能實現(xiàn)形狀記憶效應(yīng)[41,42]。Alam等[43]用—NH2官能化的碳納米管(NH2-CNTs)與PLA形成納米復(fù)合材料，5%含量的納米復(fù)合物PLA/NH2-CNTs電阻率最低，導(dǎo)電性能最好，NH2CNTs和PLA交聯(lián)程度相對較高，材料的形狀記憶性能最佳[44]。Xie等[7]也報道了一種導(dǎo)電性SMP，其良好的性能顯示了骨再生方面的潛能。他將不同鏈長度的六臂PLA化學(xué)交聯(lián)起來，之后加入了苯胺二聚體(AT)獲得了導(dǎo)電SMP，其形狀記憶過程見圖4。

圖3 不同HA含量的HA-g-PDLA納米復(fù)合物的形狀記憶行為[40]Fig.3 Shape memory behavior of HA-g-PDLA nanocomposites with different HA proportion[40]

圖4 基于星型聚乳酸和苯胺二聚體導(dǎo)電SMP回復(fù)圖解[7]Fig.4 Shape recovery diagram of SMP based on PLA and AT[7]

2 聚己內(nèi)酯基形狀記憶聚合物

聚己內(nèi)酯(Polycaprolactone，PCL)是一種半結(jié)晶性的脂肪族聚酯，酯基(—COO—)在自然條件下易被微生物或酶分解，生成小分子產(chǎn)物CO2和H2O[45-47]。線形的PCL不具有形狀記憶效應(yīng)，交聯(lián)呈網(wǎng)絡(luò)狀的PCL耐熱性能顯著提高，表現(xiàn)出形狀記憶行為。PCL的交聯(lián)固化一般分物理交聯(lián)型和化學(xué)交聯(lián)型。

2.1 物理交聯(lián)PCL

物理方法主要采用高能射線(如Co60-γ射線，紫外射線等)輻射，將聚己內(nèi)酯分子鏈破裂產(chǎn)生自由基，自由基重新結(jié)合形成交聯(lián)的網(wǎng)絡(luò)結(jié)構(gòu)。本課題組最先開始研究物理交聯(lián)PCL，Zhu等[48]對不同分子量PCL在不同溫度下的輻射交聯(lián)規(guī)律、力學(xué)性能、熱性能、結(jié)晶性和形狀記憶性能進(jìn)行了實驗研究。PCL的交聯(lián)屬于無規(guī)交聯(lián)，DMA分析表明，輻射交聯(lián)PCL的彈性模量和熱性能顯著的提高。交聯(lián)改變了PCL的結(jié)晶程度和熔點[49]。

輻射交聯(lián)存在的問題是交聯(lián)效率較低，因此本課題組將聚己內(nèi)酯與多官能團(tuán)單體共混輻射交聯(lián)，多官能團(tuán)單體的加入可以顯著提高PCL輻射交聯(lián)的效率。交聯(lián)后的PCL形狀記憶性能優(yōu)異，回復(fù)速率快。Zhu等[50]將PCL和PMVS(聚甲基乙烯基硅烷)共混后輻射交聯(lián)，實驗表明，PMVS的加入會減小PCL/PMVS共混物的裂解/交聯(lián)(p0/q0)比，提高交聯(lián)效率，交聯(lián)后形狀回復(fù)率超過95%。

2.2 化學(xué)交聯(lián)PCL

物理交聯(lián)得到的PCL交聯(lián)點隨機分布，結(jié)構(gòu)不規(guī)整。化學(xué)交聯(lián)用含有多官能團(tuán)的單體作為交聯(lián)點，將PCL偶聯(lián)成化學(xué)交聯(lián)的結(jié)構(gòu)，結(jié)構(gòu)可預(yù)先設(shè)計。

圖5 線形/網(wǎng)絡(luò)聚己內(nèi)酯共混物[46]Fig.5 Linear/network poly(ε-caprolactone) blends[46]

Rodriguez等[46]先將PCL二醇與酰氯制備了端丙烯酸酯基團(tuán)的預(yù)聚物，預(yù)聚物和多元醇在紫外光照條件下發(fā)生聚合形成網(wǎng)絡(luò)交聯(lián)結(jié)構(gòu)。在此基礎(chǔ)上，作者將線形PCL和交聯(lián)PCL共混，線形PCL貫穿整個網(wǎng)絡(luò)，獲得了一種線形/網(wǎng)絡(luò)聚己內(nèi)酯共混物(圖5)。Garle等[51]先用1，4-環(huán)己二醇和肉桂酰氯合成了肉桂?；鶊F(tuán)改性己內(nèi)酯(CCL)，然后CL和CCL開環(huán)聚合合成了半結(jié)晶型的聚己內(nèi)酯基共聚物(無規(guī)或PCL、PCCL、PCL三嵌段共聚物)。肉桂酸酯可生物降解，降解產(chǎn)物無毒，并且在紫外光作用下，肉桂酸酯中的不飽和鍵可形成化學(xué)交聯(lián)結(jié)構(gòu)，這樣聚合物具有很好的形狀記憶效應(yīng)，PCL鏈段形成結(jié)晶相，PCCL鏈形成無定型部分。

3 聚氨酯類形狀記憶聚合物

另外一種重要的醫(yī)用形狀記憶聚合物是聚氨酯類高分子，形狀記憶聚氨酯(SMPU)由多異氰酸酯(如TDI，MDI，PDI等)和可降解的多元醇或聚酯類多元醇(如PCL、PGA、聚己二酸丁二醇酯等)反應(yīng)，再以多元醇(如乙二醇、丁二醇、己二醇等)作為擴(kuò)鏈劑制備而成[52-57]。按結(jié)構(gòu)特點可將形狀記憶聚氨酯分為熱塑性SMPU，熱固性SMPU。

3.1 熱塑性可降解SMPU

熱塑性形狀記憶聚氨酯，通過氨基甲酸酯基團(tuán)的聚集(氫鍵作用)形成物理交聯(lián)點來實現(xiàn)形狀記憶功能。Ping等[58]用分子量為500～10000的PCL二醇，乙二醇和甲苯二異氰酸酯(TDI)制備生物降解性的形狀記憶聚氨酯(PCLU)，其中PCL作為軟段，TDI-EG作為硬段，軟硬段比值在1∶2到1∶6的范圍內(nèi)，材料具有形狀記憶效應(yīng)。Xue等[59]用己內(nèi)酯在丙三醇的作用下開環(huán)聚合生成預(yù)聚物(分子量為2700～4200g/mol，熔融溫度為45～47℃)，1,6-己二醇作為擴(kuò)鏈劑，預(yù)聚物和4,4-二苯基甲烷二異氰酸酯(MDI)反應(yīng)生成可降解聚氨酯(PCL-PU)。大分子纏結(jié)點也可作為物理交聯(lián)來實現(xiàn)形狀記憶效應(yīng)。

目前對熱塑性SMPU的研究主要是針對軟段多元醇的種類和相對含量對其形狀記憶性能的影響。王小鋒等[60]比較了不同軟段聚己二酸乙二酯(PEAG)、聚己二酸丁二酯(PBAG)、聚己二酸己二酯(PHAG)、聚己內(nèi)酯(PCL)形成的超支化SMPU的結(jié)晶能力和形狀記憶性能。實驗發(fā)現(xiàn)，聚酯多元醇鏈段越長，結(jié)晶越容易，其中PHAG和PBAG合成的SMPU屬于半結(jié)晶聚合物，綜合性能較好。

3.2 熱固性可降解SMPU

熱塑性形狀記憶聚氨酯循環(huán)記憶能力較差，形狀恢復(fù)力不足，熱固性SMPU具有體型交聯(lián)結(jié)構(gòu)，形狀記憶性能更好。線形聚氨酯通過多種方式交聯(lián)成網(wǎng)絡(luò)結(jié)構(gòu)[61]，如圖6。

圖6 各種不同化學(xué)交聯(lián)結(jié)構(gòu)CPUs的圖解[61]Fig.6 Scheme of CPUs with various crosslinking networks [61]

Chun等[62,63]用柔性PEG鏈段將線形PU側(cè)鏈交聯(lián)形成網(wǎng)絡(luò)結(jié)構(gòu)(圖6A)，交聯(lián)后的PU形狀固定率和形狀回復(fù)率都超過了90%。隨后Chung等[64]用較硬的聚碳酸酯二醇替代了端羥基聚四氫呋喃，二苯基甲烷二異氰酸酯(MDI)作為交聯(lián)劑，將相鄰兩個PU的側(cè)鏈連接起來(圖6B)，改進(jìn)后的聚合物拉伸強度和形狀回復(fù)率都有所提高。Xue等[65]設(shè)計了一種軟段為支化三臂PCL，硬段為微生物聚酯的形狀記憶嵌段共聚物，形成了三維網(wǎng)狀結(jié)構(gòu)(圖6C)，并將這種聚合物用于自膨脹支架。除了用有機基團(tuán)作為交聯(lián)點，無機/有機交聯(lián)SMPU網(wǎng)絡(luò)結(jié)構(gòu)的報道也越來越多。早在2004年，Cho等[66]通過溶膠-凝膠反應(yīng)將四乙氧基硅烷引入PU中，合成了PU-silica復(fù)合物，結(jié)構(gòu)如圖6D。在此基礎(chǔ)上Chung等[67]先通過形成脲基甲酸酯基團(tuán)在PU側(cè)鏈上引入3-氨丙基三乙氧基硅烷(ATS)，接著利用三乙氧基硅基基團(tuán)間的溶膠-凝膠反應(yīng)將線形PU交聯(lián)起來，如圖6E。改性的二氧化硅納米粒子也可作為PU的擴(kuò)鏈劑形成網(wǎng)絡(luò)交聯(lián)結(jié)構(gòu)，Jang等[68]將納米二氧化硅粒子作為多官能交聯(lián)劑，通過溶膠-凝膠反應(yīng)將線形PU聚合在一起，其結(jié)構(gòu)如圖6F。Zhang等[69]制備了SiO2為交聯(lián)中心的聚氨酯(圖6G)，SiO2的引入顯著增強了材料的力學(xué)性能。多面體低聚倍半硅氧烷(POSS)也可交聯(lián)PU，形成星型聚氨酯結(jié)構(gòu)(圖6H)[70]。Mya等[71]用羥基官能化的POSS粒子開環(huán)聚己內(nèi)酯，HDMI(六亞甲基二異氰酸酯)作為擴(kuò)鏈劑，制備了八臂-星型POSS-PCL聚氨酯，如圖7所示。POSS的引入從分子水平上提高了材料的熱穩(wěn)定性和力學(xué)性能，玻璃化溫度和存儲模量都有所提升。

圖7 SMP網(wǎng)絡(luò)結(jié)構(gòu)[71]Fig.7 SMP network[71]

4 展望

生物醫(yī)用形狀記憶聚合物材料不但可以充當(dāng)現(xiàn)代醫(yī)療中的一些臨時材料，如藥物緩釋體系等，而且其獨特的形狀變化還具有廣闊的應(yīng)用前景。集生物相容性、生物降解性和形狀記憶性能的聚合物材料必將是生物領(lǐng)域中最熱門的智能材料。生物醫(yī)用形狀記憶聚合物的一些研究趨勢概括如下：

(1)雙程形狀記憶效應(yīng)具有單程形狀記憶效應(yīng)不具備的應(yīng)用優(yōu)勢，而目前報道的雙程SMP卻很少，因此需要加強對這類形狀記憶材料在生物醫(yī)學(xué)方面的研究。

(2)由于生物醫(yī)用SMP需應(yīng)用于人體中，所以將轉(zhuǎn)變溫度調(diào)整至體溫的37℃附近是有必要的。目前具有該轉(zhuǎn)變溫度的生物醫(yī)用SMP的種類尚少，醫(yī)用選擇性少，因此需要研究或開發(fā)更多種類的滿足上述轉(zhuǎn)變溫度的生物醫(yī)用SMP。

(3)植入體內(nèi)的形狀記憶聚合物，不僅要研究直接或者間接的熱響應(yīng)，還要考察體液環(huán)境，pH值等對形狀記憶效應(yīng)的影響。

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(本文責(zé)編：解 宏)

Biomedical Shape Memory Polymers

SHEN Xue-lin,ZHU Guang-ming,YANG Peng-fei

(Department of Applied Chemistry,Northwestern Polytechnical University,Xi’an 710129,China)

Shape memory polymers(SMPs) are a class of functional “smart” materials that have shown bright prospects in the area of biomedical applications. The novel smart materials with multifunction of biodegradability and biocompatibility can be designed based on their general principle, composition and structure. In this review, the latest process of three typical biodegradable SMPs(poly(lactide acide), poly(ε-caprolactone), polyurethane) was summarized. These three SMPs were classified in different structures and discussed, and shape-memory mechanism, recovery rate and fixed rate, response speed was analysed in detail, also, some biomedical applications were presented. Finally, the future development and applications of SMPs are prospected: two-way SMPs and body temperature induced SMPs will be the focus attension by researchers.

biomedical;shape memory polymers;poly(lactide acide);poly(ε-caprolactone);polyurethane

10.11868/j.issn.1001-4381.2015.001230

0631；TB34

A

1001-4381(2017)07-0111-07

2015-10-14；

2016-12-16

朱光明(1963-)，男，博士研究生導(dǎo)師，研究方向：形狀記憶高分子，聯(lián)系地址：陜西省西安市西北工業(yè)大學(xué)長安校區(qū)理學(xué)院化學(xué)系(710129)，E-mail:gmzhu@nwpu.edu.cn