微球材料尺寸和结构控制的过程工程

微球材料的粒径均一性和结构可控性直接影响其应用效果,这对过程工程提出了挑战。在发展微孔膜乳化过程制备均一乳液和微球的基础上,对均一乳液的形成机理进行了研究,通过对液滴形成过程的控制,在油/水、水/油、水/油/水等体系成功制备出了均一微球。通过发展微球结构演变过程的定量研究方法,成功对微球结构进行了调控;针对生化工程对超大孔微球的重要需求,发展了超大孔微球制备方法,实现了孔径在100 nm到微米级的调控。研究了粒径均一性和结构对其应用效果的影响。微球应用于生物分离介质时,粒径均一性提高了蛋白质的分离度;超大孔微球可使超大生物分子快速进入介质内部,显著提高纯化回收率。微球应用于胰岛素口服药物载体时,粒径对其在消化道的分布有显著影响,中空-多孔微球显示了最佳的降血糖效果。     

高分子大孔微球的制备和结构控制

高分子大孔微球的形成和结构调控是一个复杂的过程,特别对于孔径超过100 nm的超大孔微球而言,无法通过常规的制孔剂与聚合物之间的相分离得到。针对生化工程对于超大孔微球的重要需求,发展了反胶团溶胀法和复乳法,实现了孔径在百纳米级以上的控制。研究了微球结构对于应用效果的影响。超大孔微球用于生物大分子的分离纯化,显示出高载量、高活性回收率、高纯化倍数的特点。超大孔微球固定化酶在酶的热稳定性、储存稳定性、重复使用性能等方面具有显著的优势。微球的结构有效控制是在不同领域获得成功应用的保障。     

复乳法制备大孔琼脂糖分离介质与疫苗结合性能研究

大孔分离介质在分离纯化特别是超大生物分子分离纯化领域具有十分重要的应用意义。受材料性质和制备技术所限制,大孔分离介质以聚合物材料最为常见,针对琼脂糖的大孔分离介质较为少见。通过复乳法制备大孔琼脂糖微球,研究制备条件对微球形貌与成孔情况以及粒径与分布等的影响,发现该微球具备微米级超大孔结构,且制备条件对孔道结构的影响呈现一定规律,琼脂糖溶液浓度、内/外油相与水相比例、初乳转速和成球转速等都对成孔性至关重要。激光共聚焦显微镜实验结果表明,衍生后的大孔琼脂糖分离介质对乙肝表面抗原具有良好的结合能力,使其能够完全进入微球内部。与传统琼脂糖介质相比,大孔琼脂糖介质能够更快速、充分结合大分子疫苗,在超大分子分离纯化领域应用前景广阔。     

复乳液滴模板法结合溶剂去除法制备P(MMA-MAA)超大孔聚合物微球

以聚(甲基丙烯酸甲酯-甲基丙烯酸)[P(MMA-MAA)]为主要微球材质,两亲性聚(乳酸-聚乙二醇)二嵌段共聚物(PELA)为辅助材质,通过复乳液滴模板法结合溶剂去除法,制备了微米尺度贯穿孔道结构的超大孔P(MMA- MAA)微球,考察了油相中材质浓度、内水相盐浓度、复乳演变时间等对微球形态及孔道结构的影响,分析了微球表面孔隙的演变机理. 在P(MMA-MAA)浓度100 g/L和PELA浓度30~40 g/L、外水相PVA浓度25 g/L、内水相NaCl浓度1~5 g/L、乳液熟化时间0~30 min的条件下,可制备出形态较好的超大孔微球,微球的表面孔径可达数微米,孔隙率最高可达95%. 超大孔微球形成后,对其骨架进行共价交联,可形成刚性微球骨架.     

尺寸均一微球制剂的研究进展

微球制剂是新型的给药系统,其粒径均一性非常重要,不仅影响产品批次间制备重复性,还会影响应用效果。因此,尺寸均一、可控的微球产品是医药制剂的关键核心。本团队成功发展了微孔膜乳化技术,20年来在粒径均一、尺寸可控微球的制备和应用方面进行了系统性研究。均一的微球制剂的优势有：绿色环保、降低成本,利于规模放大,批次间重复性好,利于研究构效关系。本团队制备的均一载药微球已成功应用于缓释制剂、疫苗递送及恶性肿瘤治疗中。     

无皂乳液聚合法合成单分散性阴离子聚苯乙烯微球

采用无皂乳液聚合法制备了粒径大小可控且均一的聚苯乙烯微球,研究了反应过程中SDS加入量、反应温度、引发剂加入量及反应介质对聚苯乙烯微球粒径大小及分布的影响。利用傅立叶变换红外光谱仪对微球结构进行了表征。     

表面羧基化聚丙烯酸酯多孔微球的制备及其铜离子吸附性能研究

以浓乳液作为悬浮聚合的油相,采用水（W）/油（O）/W浓乳液/悬浮聚合方法制备出了内部具有通孔结构、粒径均一的聚甲基丙烯酸叔丁酯多孔微球。结果表明,通过研究乳化剂含量、搅拌速度等参数对多孔微球的内部微孔形貌与微球粒径的影响,发现当乳化剂含量为4 %时,得到的聚合物微球内的微孔结构分布均匀;而聚合物微球的平均粒径会随着搅拌速度的增大而减小。将不同粒径的多孔微球进行酸化水解后得到了表面羧基官能化的聚合物多孔微球,利用其丰富的通孔结构实现了对铜离子（Cu²⁺）的有效吸附,当微球平均粒径介于200~300 μm时,铜离子的去除率最高,可达99.3 %。     

快速膜乳化法制备胸腺法新长效缓释微球

采用快速膜乳化技术结合溶剂蒸发法制备以生物可降解聚乳酸-羟基乙酸(PLGA)为载体的胸腺法新载药微球,考察了PLGA分子量、油相中PLGA和乳化剂浓度、外水相pH值和内水相体积等对微球包埋率和粒径的影响. 结果表明,制备粒径均一的PLGA载药微球的优化条件为：PLGA分子量51 kDa,油相中PLGA和乳化剂浓度为100和10 g/L,内水相体积0.5 mL,外水相pH值为3.5. 该条件下所制载药微球粒径均一性好(Span<0.7),药物包埋率高达80%以上,突释率24 h内低于20%,线性持续稳定释药时间长达30 d.     

羧基磁性高分子微球的制备和表征

用改进的悬浮聚合法制备了表面含有羧基功能团的聚苯乙烯磁性微球。考察了磁微球的形态与结构 ,测定了磁微球的粒径与磁响应性 ,主要研究了单体 /水、丙烯酸 /单体、反应温度和反应时间对磁性微球形成的影响 ,并对磁性微球的生物吸附活性进行了表征。优化得到了制备具有良好生物吸附活性的羧基磁性微球的最佳实验条件     

用于单克隆抗体纯化的仿生多肽超大孔PGMA微球制备及其性能

以仿生多肽配基FYEILHC为亲和配基、以葡聚糖修饰的聚甲基丙烯酸缩水甘油酯[Dextran-poly(glycidyl methacrylate), Dextran-PGMA]超大孔微球为基质，制备用于单克隆抗体纯化的仿生多肽超大孔PGMA微球，在环氧氯丙烷中滴加2 mol/LNaOH使其表面衍生出环氧基，在表面修饰FYEILHC；用扫描电镜表征微球表面形貌，用AKTA蛋白纯化系统考察了Dextran-PGMA微球和琼脂糖微球对抗体的动态吸附量随线性流速的变化。结果表明，偶联FYEILHC后Dextran-PGMA微球仍能保持其大孔结构，在923 cm/h线性流速下，其对抗体的动态吸附量仅下降约8%，而琼脂糖微球的动态吸附量则迅速下降25%。表明在较高流速下，抗体在Dextran-PGMA微球上的传质性能较好。吸附?用0.1 mol/L NaOH原位清洗重复40次后，Dextran-PGMA微球对抗体的动态吸附量约为(21?1) mg/mL，表明微球具有良好的化学稳定性；血清中回收的抗体纯度为95.0%，表明仿生多肽亲和介质具有从复杂生物样品中纯化抗体的巨大潜力，可满足高流速、高通量抗体分离纯化需求。     

Fabrication and structural regulation of PLLA porous microspheres via phase inversion emulsion and thermally induced phase separation techniques

In this work, a facile, scalable technique was developed to produce biodegradable porous microspheres by combining an oil‐in‐oil (O/O) surfactant‐free phase inversion emulsion technique with thermally induced phase separation (TIPS) method. The effects of PLLA concentration, stirring speed, macromolecule weight, and organic solvents on the size and microstructure of microspheres were investigated by scanning electron microscopy (SEM). The results revealed a highly porous structured microsphere with controllable sizes and morphologies by tuning the synthesis conditions. The typical resulting PLLA microspheres consist of nanoscale topographic structured surface and highly microporous interior. The coarse nanotopography and microcellular inner structure lead to a high drug loading capacity up to 60% for the PLLA microspheres from THF. The cumulative release percentage of the ibuprofen could reach 80% for drug‐loaded microspheres with different microstructures. The fabricated PLLA microspheres would have potential applications in the field of drug delivery and tissue engineering. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44885.     

纳米聚合物微球的封堵性及驱油性能

聚合物纳米微球因其对水、温度和矿化度具有良好抵抗力以及较低的使用成本而受到更多关注,作为一项新型调驱技术,可大幅提高油田采油效率。为了更好地认识聚合物纳米微球的驱油效果,开展了聚合物纳米微球的封堵及驱油研究。进行了微通道驱替实验,透过滤膜实验,通过激光粒度仪分析了溶胀后微球的尺寸变化,通过透射电镜观察了微球乳液,并研究了空气中微球乳液与干粉的表面张力。结果显示,在50和100 nm微球的微通道实验中都观察到了微米级别的团聚物,扩大了水分散体系的波及体积,2种纳米聚合物微球都会出现一定程度的团聚行为,具有溶胀性能,还发现了微球和乳化剂、油滴之间的缠结现象。微球乳液中含有的表面活性剂使其表面张力降低,从而提高了驱油效率。对纳米微球的封堵性能和驱油性能进行了研究,对揭示纳米微球的驱油机理和产品的可持续发展与创新具有显著意义。     

天然多糖微球的制备及功能应用

多糖微球不仅具有生物相容、无毒性、可再生等优点,还可以通过改性或者与其他功能组分巧妙结合赋予其更加多样化的功能,结合本身独特的3D球型多孔结构,多糖微球可以作为微反应器、微分离器、微结构单元等,应用涉及人们生活的方方面面。本文综述了近年来多糖微球功能材料的研究进展,首先介绍了以滴定法和乳化法及其衍生方法制备粒径均一多糖微球的进展,然后着重介绍了多糖微球的功能化构建策略及其在吸附分离、催化剂载体、组织工程与药物释放、能源转化与储存四个领域的应用进展,最后讨论了多糖微球功能材料在面向以上应用过程中仍然需要解决的关键科学问题,包括粒径均一多糖微球的规模化制备和多糖孔结构的可控制备。为今后高性能多糖微球材料的研制及应用提供有价值的参考和指导。     

How to circumvent untoward drug crystallization during emulsion‐templated microencapsulation process

Unwanted drug crystals often form on the surface of PLGA microspheres or in an aqueous phase when a hydrophobic drug undergoes emulsion‐templated microencapsulation processes. In our study, over 70% of progesterone crystallizes in the aqueous phase when microencapsulation proceeds with a typical oil‐in‐water solvent evaporation process. During filtration employed for microsphere recovery, unentrapped drug crystals are collected alongside with progesterone‐containing microspheres. This phenomenon accompanies unfavorable consequences on the microsphere quality. In contrast, when microspheres are prepared with a new solvent extraction‐evaporation hybrid process, it is possible to completely avoid drug crystallization. Consequently, the new microencapsulation technique yields high drug encapsulation efficiencies of ≥ 90.8%, and the resultant microspheres show a homogeneous size distribution pattern. Also, the microsphere surface is free of drug crystals. For loading hydrophobic drugs into PLGA microspheres, the new microencapsulation process reported in this study has distinct advantages over commonly used emulsion‐templated solvent evaporation processes. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43768.     

乳液法结合溶胶-凝胶法制备多孔TiO2微球

为了进一步提高二氧化钛（ TiO₂）的反射率,采用乳液法结合溶胶 -凝胶法,以聚乙二醇（PEG）为相分离诱导剂,制备了内部具有不连续多孔结构的 TiO₂微球。考察了 PEG的添加量对 TiO₂微球内部孔径大小的影响。研究结果表明： TiO₂微球内部的孔径随 PEG的用量增加而增大。基于溶胶-凝胶转变和相分离过程,详细介绍了多孔 TiO₂微球的形成机理。当 PEG的添加量为 9.0%时,所制备的多孔 TiO₂微球在近红外区的积分平均反射率为 84.9%,比常见钛白粉提高了 5.4%。     

The influence of water on size of the monodisperse polystyrene microspheres prepared by dispersion polymerization

Polystyrene microspheres with uniform sizes have a wide range of applications in biomedical engineering. However, detailed and systematic investigations on the influence of water content on alcohol/water systems are relatively scarce. In this study, the impact of trace water content on microsphere size was comprehensively examined, and a systematic exploration of the varying effects of different hydration levels on particle nucleation and growth mechanisms was conducted. When the water content increased from 0.1% to 0.4%, the microsphere diameter rapidly decreases from 3.6 to 2.71 μm. Correspondingly, the molecular weight increased from 29,797 to 69,186. However, within the water content range of 0.5%–14.5%, alterations in water content induced only slight variations in the microsphere diameter. The microsphere size, molecular weight, conversion rate, and reaction rate were compared in two stages. It was observed that the diminishing influence of water on the system was due to the changes in the main polymerization sites. Subsequently, the addition of water content up to 33.5% revealed an exponential decrease in the microsphere size with increasing water content in ethanol. This pattern was also observed in methanol and isopropanol, demonstrating its universality and predictability, making it applicable for precise prediction of microsphere size in different solvents.     

Chitosan‐g‐Polyester Microspheres: Effect of Length and Composition of Grafted Chains

Hydrophobic segments made of oligo(l,l ‐ or d,l ‐lactides) or poly(l,l ‐lactide) are grafted onto chitosan backbone in order to use their amphiphilic behavior to prepare degradable microcarriers intended to be used for tissue engineering. Hydrophilic–lipophilic balance of these copolymers is adjusted playing on the respective length of their hydrophilic and hydrophobic moieties. Thanks to their self‐emulsifying properties, these graft copolymers are processed into microspheres in the absence of hydrophilic emulsifier commonly added in the aqueous phase of the oil/water emulsion. The copolymers containing amorphous oligolactide segments of medium length are demonstrated to be the most effective ones for microparticle fabrication. The microparticles are characterized using SEM, EDX, and FTIR. The reactivity of amine group is demonstrated using fluorescein isothiocyanate staining. The resulting microspheres disclose a porous core and a shell enriched by the hydrophilic polysaccharide moieties. Stabilization of the oil/water interface during the microsphere fabrication, total yield, size distribution, and microparticle surface morphology are mainly affected by the macromolecular features of the copolymers.     

Preparation of polysulfone microspheres with a hollow core/porous shell structure and their application for oil spill cleanup

Polysulfone (PSF) microspheres with a hollow core/porous shell structure were prepared by a water‐in‐oil‐in‐water emulsion solvent evaporation method. The morphology of PSF could be controlled by variation of the surfactants, which included oleic acid, poly(vinyl pyrrolidone), and tween 80. The three kinds of prepared microspheres were developed as sorbents for the selective removal of oil from water. PSF microspheres with a hollow core/porous shell structure exhibited the best separation efficiency, which was 44.8 times higher than that of the pristine PSF powder. The oil‐absorbed microspheres combined with unsinkability, appropriate size, and highly hydrophobic and superoleophilic properties could be quickly distributed and collected in seconds and exhibited recyclability. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Multihollow nanocomposite microspheres with tunable pore structures by templating Pickering double emulsions

Micrometer-sized dual nanocomposite polymer microspheres with tunable pore structures were fabricated using a simple and straightforward method based on Pickering double emulsions. First, a primary water-in-styrene (oil) emulsion (w₁/o) was prepared using the hydrophobic silica nanoparticles as a particulate emulsifier without any molecular surfactants. Then, a water-in-styrene-in-water (w₁/o/w₂) Pickering emulsion was produced by the emulsification of the primary w₁/o emulsion into water using Fe₃O₄ nanoparticles as external emulsifier. The big styrene droplets containing small water droplets were polymerized after the formation of the double emulsions. Nanocomposite polystyrene microspheres with a multihollow structure were obtained and their morphological structures were studied by scanning electron microscopy (SEM). The pore structure of the microspheres could be tuned by the volume ratio of the internal water phase to the medium oil phase (w₁:o) of the primary emulsions. With increasing w₁:o from 1:8 to 4:1, the amount of the pores in one microsphere increased gradually and the pore structures changed from close to interconnected. The resulting multihollow microspheres had a responsive ability to magnetic stimulus due to the existence of Fe₃O₄ nanoparticles. This kind of multihollow hybrid polymer microspheres is expected to have a wide potential application in materials science and biotechnology.