摘要
骨组织工程为广大骨病患者提供了新的途径和希望。其中组织再生支架材料的设计是骨组织工程成功的关键，通常要求它满足一定的力学强度、可控的降解性能和合理的表面诱导细胞增殖分化及组织再生。然而，目前很少有材料能同时具备以上性能。本研究的目的是设计一种新型的骨组织工程材料，使其集可控降解性能、一定的力学强度、适当的亲水性能及可功能化的表面等性能于一身。基于PEG衍生物聚（乙二醇-co-均苯四甲酸酐）亚胺（PAPI）与D,L-丙交（D,L-LA）酯共聚，制备了一系性能可调的PAPI-PDLLA新型共聚物。采用核磁共振（NMR）、傅立叶变换红外光谱仪（FTIR）、凝胶色谱-十八角激光散射仪（GPC-MALLS）、紫外可见光谱仪（UV）、示差扫描量热仪（DSC）、X光电子能谱（XPS）、扫描电镜（SEM）、原子力显微镜（AFM）等对共聚物的化学物理性能进行了表征；详细考察了PAPI-PDLLA共聚物的亲/疏水性、体外生物降解性能、力学性能（拉伸性能和压缩性能），以及降解过程中的力学性能变化；对PAPI-PDLLA共聚物的表面进行了氨基和羟基功能化研究；最后，评价了PAPI-PDLLA共聚物及表面功能化材料的体外细胞生物相容性。研究的主要内容和结论如下：
1.较低分子量的氨基封端的PEG（ATPEG，Mr:900）与均苯四甲酸酐（PMDA）通过高温缩聚反应合成出新型PEG衍生物P(ATPGE-co-PMDA)(PAPI)。在合成条件的优化实验中，考察了单体比例、温度、反应时间等对聚合物分子量的影响和反应过程中酰亚胺化的程度等；该衍生物通过苯酰亚胺环连接，酰亚胺环的引入为开环功能接枝提供了条件，研究了丁二胺、乙醇胺与PAPI中酰亚胺环反应的能力；对所有合成的材料结构进行了表征。
①FTIR、1H NMR、13C NMR、GPC-MALLA和UV检测结果表明，ATPEG与PMDA成功聚合，ATPEG的微过量使得合成的PAPI端部具有氨基。当二者的摩尔比ATPEG/PMDA=1.05时，在设定的梯度高温温度下反应完成后，酰亚胺化基本完全，所获得的聚合物分子量较大，聚合物分散系数较低。热重分析表明PAPI相对于PEG的热稳定性增强。
②FTIR表明，PAPI中酰亚胺环在室温无催化剂下成功与丁二胺和乙醇胺反应，可能为接枝功能基团提供反应位点。
③在与丁二胺反应时，发生了交联，快速产生了凝胶，该凝胶具有一定的力学强度和多孔性，有望应用于药物释放或组织工程领域。
2.PAPI和辛酸亚锡共引发体系引发D,L-丙交酯开环，合成了一系列PAPI-PDLLA共聚物，研究了PAPI/D,L-丙交酯、反应温度、反应时间等对PAPI-PDLLA共聚物分子量的影响，并表征了其化学结构和热性能。
①FTIR、1H NMR、13C NMR和GPC-MALLS的结果表明，PAPI的端氨基和辛酸亚锡共引发体系成功引发丙交酯开环，制备了PAPI-PDLLA共聚物，最佳反应时间为36小时，反应温度为150℃。
②通过调节PAPI与D,L-丙交酯的物料比，可以制备一系列不同分子量和性能的共聚物，通过1H NMR计算了接枝的聚乳酸的量；随着PAPI/D,L-丙交酯比例的增加，接枝的聚乳酸分子量下降。
③DSC结果表明，PAPI-PDLLA共聚物只有一个玻璃化转变温度，这表明两相热相容性良好，随着PAPI所占比例的增加，玻璃化温度下降。热重分析结果表明，PAPI-PDLLA出现两个明显分解温度，首先是PDLLA嵌段分解，然后是PAPI的分解，通过热重分析可以得出两嵌段的质量比。
3.研究了PAPI-PDLLA共聚物的亲/疏水性能和降解性能。亲/疏水性能采用材料表面静态水接触角和整体吸水率两种方法来评价；通过失重率、分子量变化、pH值变化和降解后样品表面形貌的变化等来评价材料的降解性能。
①亲/疏水性能测试结果表明，PAPI-PDLLA共聚物的静态水接触角均小于PDLLA，吸水率都大于PDLLA，且随着共聚物中亲水嵌段PAPI比重的增加，亲水性能增加。
②PAPI-PDLLA共聚物的体外降解实验表明，PAPI-PDLLA系列样品在降解前五周的失重、分子量下降及pH值变化相对于PDLLA对照组都要快些，但在整个降解过程中发现，PDLLA由于降解过程中酸性积累导致的自催化作用引起了陡降现象，而在PAPI-PDLLA系列材料中，降解速率较为可控，降解的失重率的自然对数与时间经拟合，发现符合假一级动力学模型Mnmolecular，没有陡降现象产生。这是由于亲水嵌段PAPI的引入，加速了降解的酸性小分子的扩散，没有导致材料明显的自催化降解作用。通过降解后的扫描电镜显示，PDLLA会产生局部不均匀降解，而PAPI-PDLLA共聚物的降解表面较为均一。因此，相对于PDLLA，材料的降解可控性能提高。
4.采用拉伸和压缩测试考察了材料的力学性能。结果表明，共聚物都具有一定的拉伸强度和压缩强度，并且强度随着PAPI/D,L-丙交酯的物料比减少而增加，而断裂伸长率随着PAPI/D,L-丙交酯的物料比的增加而显著增加。合成的共聚物拉伸模量在48-280MPa之间。压缩模量在108-780MPa之间，与松质骨的压缩模量较为匹配。随着材料的降解，材料的力学强度逐渐损失，且随着PAPI在共聚物中占的比重提高，力学损失加速，PAPD4/15（即PAPI-PDLLA中PAPI/D,L-LA=4/15)降解四周后，拉伸性能几乎全部损失，而PAPD4/25仅损失了20%左右。
5.采用湿法化学法，在PAPI-PDLLA共聚物膜表面引入了氨基和羟基，采用XPS、比色法、AFM等方法定性定量表征了材料表面接枝的氨基和羟基。在无催化剂、常温等反应条件下，在材料表面易引入氨基和羟基，这为后续的材料表面活性分子接枝提供了基础。PAPD4/15-BDA材料表面接枝的氨基密度达3.41×10~(-6)mol/cm~2。当接枝氨基和羟基后，材料表面相对于反应前变得粗糙。
6.采用大鼠乳鼠成骨细胞为种子细胞评价了PAPI及PAPI-PDLLA的细胞毒性。从成骨细胞形态、粘附、铺展、增殖、分化和矿化等几个方面系统的比较了PAPI-PDLLA及功能化表面与PDLLA的细胞相容性。
①采用PAPI浸泡液及PAPI和PAPI-PDLLA降解可能产生的最大量的PMDA的浸泡液用于培养成骨细胞，发现成骨细胞在上述培养液中培养均体现正常形态，PAPI及含PMA的培养液并不影响细胞的形态与增殖，这说明了PAPI及PAPI-PDLLA无明显细胞毒性。
②与PDLLA相比，适当的引入PAPI促进了成骨细胞的粘附与铺展，而过多的PAPI不利于细胞的粘附；功能化的PAPI-PDLLA膜表面也有利于细胞的粘附与铺展，氨基功能化的表面细胞粘附最为明显。
③相对于PDLLA，适当PAPI含量的PAPI-PDLLA膜有利于细胞增殖，而氨基和羟基功能化的表面使细胞增殖更为显著。
④成骨细胞在材料表面的分化和矿化能力采用碱性磷酸酶、无机钙分泌和胶原分泌等指标来衡量。结果表明，细胞在氨基功能化的PAPI-PDLLA膜表面的分化矿化能力略优于PAPI-PDLLA，而在PAPI-PDLLA膜上的分化矿化能力要优于PDLLA。
Bone tissue engineering brings new hope for many patients suffering bone diseasesas it will provide a new way to treat trauma, fracture or defect. The design of boneregeneration material is a key factor for the success of bone tissue regeneration. Thematerial should meet with several basic demands such as certain mechanical strength,controllable biodegradation and reasonable surface properties. However, there are fewmaterials suitable for bone tissue engineering. The aim of this study is to design andsynthetic a novel bone tissue engineering material, which can integrate the advantagesof certain mechanical property, controllable degradation, hydrophilicity and feasiblesurface functional modification. Based on a novel PEG derivate-poly (amino terminatedpolyethylene glycol-co-pyromellitic dianhydride) imide (PAPI) copolymerization withD,L-lactide (D,L-LA), a series of PAPI-PDLLA copolymer with adjustable propertieswere synthesized. The structure of the copolymers was characterized by nuclearmagnetic resonance spectrometer (NMR), Fourier transform infraredspectrometer(FTIR), Ultraviolet-visible spectrometer (UV), Gel permeationchromatography with multi-angle laser light scattering (GPC-MALLS), Differentialscanning calorimeter (DSC), Scanning electron microscopy (SEM), Atomic forcemicroscope (AFM), and X-ray photoelectron spectrometer(XPS). Then, thehydrophilicity/hydrophobicity and biodegradation of PAPI-PDLLA copolymers weresystemically examined. And the mechanical property and mechanical property duringdegradation of the copolymer were evaluated by tensile testing and compression testing.Furthermore, amino groups and hydroxyl groups were grafted on the surface ofcopolymers. Finally, the cell biocompatibility of the copolymers was evaluated. Themain works and conclusions of this study were listed as follows:
1． A novel PEG derivate PAPI was synthesized by polycondensation ofamino-terminated polyethylene glycol (ATPEG) and PMDA. The reaction conditionwas optimized. An extensive effort was expended in investigating the effects of themolar ratios of monomers, reactive time and temperature on the molecular weight. Theimide process was monitored during the reaction. The introduced imide rings in thepolymer provided reactive sites to graft functional groups. The possibility of PAPIreaction with BDA and EtA was evaluated. The structure of PAPI was characterized.
①FTIR,~1H NMR,~(13)C NMR, GPC-MALLS and UV demonstrated that thepolymerization of ATPEG and PMDA was successful. When the molar ratio of ATPEGand PMDA is1.05, the molecular weight of the polymer reached higher and all theamides in the polymer turned imides almost completely after reaction at the set gradienttemperature and time. Thermal gravity (TG) analysis suggested that the thermal stabilityof PAPI improved compared with PEG.
②FTIR verified that the imide rings of PAPI were successfully reacted with BDAand EtA without catalysis under room temperature, that means imide rings in PAPI canprovide reactive site for grafting functional groups.
③A gel was generated quickly when BDA added into PAPI solution. The gelshowed multi-pore and certain mechanical strength, having promising to apply in drugdelivery and tissue engineering.
2. PAPI-PDLLA copolymers were prepared by the melt ring-openingpolymerization of D,L-lactide under the co-initiated system of PAPI and Sn (Oct)2.Effects have been done to understanding the reaction mechanism, the dosage, thetemperature and the reaction time towards the molecular weight. The structure andthermal property of copolymers were analyzed.
①FTIR,~1H NMR,~(13)C NMR and GPC indicated that PAPI-PDLLA copolymerswere obtained successfully under the co-initiator of PAPI-NH2and Sn (Oct)2. Theoptimization condition of the ring-opening copolymerization was that the reaction wasperformed under vacuum condition at150℃for36h.
②A series of PAPI-PDLLA copolymer with different molecular weight wereprepared by varying the ratio of PAPI/D, L-lactide. The molecular weight of the graftedPDLLA in the copolymer was calculated by1HNMR. The PAPI-PDLLA copolymerswith different components and molecular weight have different physicochemicalproperties, which can be adjusted for the best application in bone tissue regeneration.
③The data of DSC shown that the PAPI-PDLLA copolymers exhibited only a glasstransition temperature (Tg), and Tg decreased with the increased of feed ratio ofPAPI/D,L-lactide. The TG curve presented that the copolymers have two decomposedtemperature: The first turning point indicated PDLLA segment decomposed, then, PAPIdecomposed. Therefore, according the TG records, the weight ratio of the two segmentsin the copolymers can be calculated.
3. The hydrophilicity/hydrophobility and biodegradation property of PAPI-PDLLAcopolymers were evaluated. Both of the static contact angle and water absorption were used to estimate the hydrophilic/hydrophobic ability of the PAPI-PDLLA copolymers.While in vitro biodegradation of PAPI-PDLLA copolymers was investigated by weightloss ratio, molecular weight changing, pH and the surface morphology variation duringdegradation.
①Water absorption of PAPI-PDLLA copolymers was more than PDLLA controlsand the static water contact angle was smaller than PDLLA controls. The reason is thehydrophilic PAPI segment into PAPI-PDLLA could bind more water molecular.Therefore, the hydrophilicity of PAPI-PDLLA copolymers is better than PDLLA.Meanwhile, the hydrophilicity of PAPI-PDLLA copolymers is elevating by theincreasing the feed ratio of PAPI segment in copolymers.
②Hydrolytic degradation of PAPI-PDLLA copolymers was lasted for12weeks.The data illustrated that the degradation of PAPI-PDLLA copolymers during the first5weeks was more rapidly than PDLLA controls. However, the weight loss, molecularweight and pH values PDLLA controls degraded significantly after degradation4-6week due to the degraded acid substances accumulation leading to acid catalyzedauto-accelerating degradation. During the whole degradation process, the PAPI-PDLLAcopolymers exhibited more controllable degradation and the degradation speed ofPAPI-PDLLA can be fitted by Mnmolecular model. The reason is the hydrophilicsegment PAPI in copolymers can accelerate the acidic material diffusion during thePDLLA segment degradation without resulting in acid auto-catalyzed degradation. Thesurface morphology of PAPI-PDLLA copolymers also showed more uniformdegradation than PDLLA.
4. The mechanical property of the copolymers was tested by tensile andcompression experiments. The results illustrated the materials exhibited certain tensilestrength and compression strength and the strength raised with the feed ratio ofPAPI/D,L-lactide decrease. The tensile modulus of copolymers was adjusted in therange of48.8to280MPa, and the compression modulus in the range of108to780MPa,which is much match with the cancellous bone. During the degradation, the mechanicalproperty of the materials is loss and the speed is rapid with the feed ratio of PAPIincreasing. After degradation for4weeks, the mechanical property of PAPD4/15istotally loss, but PAPI4/25is only loss about its25%.
5. The surface of PAPI-PDLLA member was grafted functional groups-aminogroups and hydroxyl groups by wetting chemistry. The grafted amino groups andhydroxyl groups were characterized qualitatively and quantitatively by XPS, colorimetric method, and AFM The surface amino group density of PAPI-PDLLAcopolymer reached3.41×10~(-6)mol/cm~2for PAPD4/15-BDA material by colorimetricmethod. The surface morphology of the PAPI-PDLLA copolymer became rough afterreaction with BDA and EtA.
6. The cytocompatibility of PAPI precursor and PAPI-PDLLA copolymers wasstudied by empolying primary SD rat osteoblasts as the model cells and PDLLA ascontrol. The osteoblasts morphology, attachment and spreading, proliferation,differentiation and mineralization ability were detected to evaluate the cytocompatibilityof PAPI-PDLLA copolymers. The results are following:
①Osteoblasts cultured in the PAPI soaking culture medium shown no apparentdifferences in cell morphologies and cell proliferation compared to black controls. Andosteoblasts cultured in PMA dissolved medium also exhibited normal morphology anddid not affect cell proliferation. The amounts of PMA were based on the maximumamounts that could be released from0.2g of completely degraded polymer. All theresults indicated that the PAPI and PAPI-PDLLA are no cytotoxicity.
②Compared to PDLLA, a certain amount of PAPI introduced into PAPI-PDLLAcopolymers could promote osteoblasts adhesion and spreading, but a large of PAPI inthe PAPI-PDLLA such as PAPD4/15was unfavorable for cell adhesion and spreadingbecause the hydrophilicity of the material is too strong leading to detriment of celladhesion. The functional surface of the copolymers is benefit for cell adhesion andspreading. The cell adhesion on amino group functional surface had significantimprovement contrast to other samples.
③A certain amount of PAPI introduced into PAPI-PDLLA copolymers (i.e.PAPD4/20) and their functional surface are favor to osteoblasts proliferation.
④PAPI-PDLLA copolymers member and the amino and hydroxyl groupsfunctional surfaces stimulated osteoblasts differentiation and mineralization, whichwere reflected by the production of ALP, mineralization and the expression of collagen.And the order of priority of the copolymers for differentiation and mineralization isPAPD-NH2, PAPD-OH, PAPD4/20, and PDLLA.
引文
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