The effect of cross-linking on the microstructure,mechanical properties and biocompatibility of electrospun polycaprolactone–gelatin/PLGA–gelatin/PLGA–chitosan hybrid composite

Abstract

In this study, multilayered scaffolds composed of polycaprolactone (PCL)–gelatin/poly(lactic-co-glycolic acid) (PLGA)–gelatin/PLGA–chitosan artificial blood vessels were fabricated using a double-ejection electrospinning system. The mixed fibers from individual materials were observed by scanning electron microscopy. The effects of the cross-linking process on the microstructure, mechanical properties and biocompatibility of the fibers were examined. The tensile stress and liquid strength of the cross-linked artificial blood vessels were 2.3 MPa and 340 mmHg, respectively, and were significantly higher than for the non-cross-linked vessel (2.0 MPa and 120 mmHg). The biocompatibility of the cross-linked artificial blood vessel scaffold was examined using the MTT assay and by evaluating cell attachment and cell proliferation. The cross-linked PCL–gelatin/PLGA–gelatin/PLGA–chitosan artificial blood vessel scaffold displayed excellent flexibility, was able to withstand high pressures and promoted cell growth; thus, this novel material holds great promise for eventual use in artificial blood vessels.     

Optimized Formulation of High-Payload PLGA Nanoparticles Containing Insulin–Lauryl Sulfate Complex

A novel poly(lactic acid-co-glycolic acid) nanoparticle loaded with insulin–lauryl sulfate complex was prepared by spontaneous emulsion solvent diffusion method. The effects of key parameters such as agitation speed, poly(vinyl alcohol) concentration, solvent composition, polymer concentration, and the volume of external aqueous phase on the properties of the nanoparticles were investigated. To enhance the drug recovery and drug content simultaneously, a response surface methodology with five-level, two-factor central composite design was employed. The weight ratio of polymer to drug and volume ratio of external aqueous phase to solvent phase were selected as controlled factors on account of their interactions found in the monofactorial investigations. The experimental datum allowed the development of quadratic models (p < .05) describing the inter-relationships between the dependent and independent variables. By solving the regression equation, and graphic analyzing the response surface contour and plots, the optimum values of the two factors were determined as 20/1 and 10/1. The optimized conditions led to 89.6% of drug recovery and 4.57% of drug content during nanoparticle preparation.     

Synthesis and characterization of MeO–PEG–PLGA–PEG–OMe copolymers as drug carriers and their degradation behavior in vitro

The objective of this study was to characterize the methylpoly (ethylene glycol)-poly (lacticacid-co-glycolicacid)-poly (ethylene-glycol) (MeO-PEG-PLGA-PEG-OMe, abbreviation as PELGE) copolymers as intravenous injection drug delivery carriers and their degradation behavior in vitro. A series of MeO-PEG-PLGA-PEG-OMe copolymers with various molar ratios of lactic to glycolic acid and various molecular weights and different MeO-PEG contents were synthesized by ring-opening polymerization in the presence of MeO-PEG with molar masses of 2000 and 5000, using stannous octoate as the catalyst. The hydrophilicity of PELGE copolymers, evaluated by contact angle measurements, was found to increase with an increase in their MeO-PEG contents. Methylpoly (ethylene glycol)-poly (lacticacid-co-glycolicacid) (MeO-PEG-PLGA, abbreviation as PELGA) nanoparticles and PELGE nanoparticles were prepared using the emulsion-solvent evaporation technique (o/w) with Pluronic F68 (Poloxamer 188 NF) as emulsifier in the external aqueous phase. The degradation behavior of the nanoparticles was evaluated by the lactate generation with time upon their in vitro incubation in PBS (pH 7.4). The rate of in vitro degradation of the PELGE or PELGA nanoparticles depended on their composition, increasing with an increase in the proportion of MeO-PEG or LA in the copolymer chains. The degradation rate was slower at higher lactide: glycolide ratio. The lower the molecular weight of PELGE; the higher the degradation rate of the nanoparticles.     

Porous nano-hydroxyapatite/collagen scaffold containing drug-loaded ADM–PLGA microspheres for bone cancer treatment

To develop adriamycin (ADM)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles in a porous nano-hydroxyapatite/collagen scaffold (ADM–PLGA–NHAC). To provide novel strategies for future treatment of osteosarcoma, the properties of the scaffold, including its in vitro extended-release properties, the inhibition effects of ADM–PLGA–NHAC on the osteosarcoma MG63 cells, and its bone repair capacity, were investigated in vivo and in vitro. The PLGA copolymer was utilized as a drug carrier to deliver ADM–PLGA nanoparticles (ADM–PLGA–NP). Porous nano-hydroxyapatite and collagen were used to materials to produce the porous nano-hydroxyapatite/collagen scaffold (NHAC), into which the ADM–PLGA–NP was loaded. The performance of the drug-carrying scaffold was assessed using multiple techniques, including scanning electron microscopy and in vitro extended release. The antineoplastic activities of scaffold extracts on the human osteosarcoma MG63 cell line were evaluated in vitro using the cell counting kit-8 (CCK8) method and live-dead cell staining. The bone repair ability of the scaffold was assessed based on the establishment of a femoral condyle defect model in rabbits. ADM–PLGA–NHAC and NHAC were implanted into the rat muscle bag for immune response experiments. A tumor-bearing nude mice model was created, and the TUNEL and HE staining results were observed under optical microscopy to evaluate the antineoplastic activity and toxic side effects of the scaffold. The composite scaffold demonstrated extraordinary extended-release properties, and its extracts also exhibited significant inhibition of the growth of osteosarcoma MG63 cells. In the bone repair experiment, no significant difference was observed between ADM–PLGA–NHAC and NHAC by itself. In the immune response experiments, ADM–PLGA–NHAC exhibited remarkable biocompatibility. The in vivo antitumor experiment revealed that the implantation of ADM–PLGA–NHAC in the tumor resulted in a improved antineoplastic effect and fewer adverse side effects than direct intraperitoneal injection of ADM. The ADM–PLGA–NHAC developed in this study exhibited excellent extended-release drug properties, bone repairing and antineoplastic efficacy, which make it a promising osteoconductivity material with the capability to inhibit osteosarcoma.     

5-Fluorouracil-loaded PLA/PLGA PEG–PPG–PEG polymeric nanoparticles: formulation,in vitro characterization and cell culture studies

In this study, 5-FU, a potent anticancer drug, is planned to be delivered via a new and promising drug delivery system, nanoparticles formed with hydrophobic core polymer and triblock copolymers; Poly(DL-lactic acid), Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer (PLA/PEG-PPG-PEG) and Poly(D,L-lactide–co-glycolide)/Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer (PLGA/PEG-PPG-PEG) nanoparticles. Particle size range of nanoparticles was found to be between 145 and 198?nm, which would promote the passive targeting of the nanoparticles to tumor cells based on the enhanced permeability and retention (EPR) effect. SEM images revealed all nanoparticles formulations to be spherical and without pores. Zeta potential, yield value and encapsulation efficiencies of 5-FU-loaded nanoparticles were within the range of ?11.1 and ?13.7?mV, 72.7–87.7% and 83.6–93.9%, respectively. Cumulative release of 5-FU was observed between 90% and 94.4% in all nanoparticle formulations by the end of 72?h, and fitness of release profiles to Higuchi model indicated matrix-controlled diffusion of the 5-FU from polymeric nanoparticles. Cell viability values of the cells treated with 5-FU-loaded nanoparticles were obtained as low as 47% and 52% with tetrazolium dye assay, suggesting that delivery of 5-FU via amphiphilic triblock copolymer nanoparticles would be a promising delivery system because of the EPR effect.     

A novel risperidone-loaded SAIB–PLGA mixture matrix depot with a reduced burst release: effects of solvents and PLGA on drug release behaviors in vitro/in vivo

The purpose of this study was to develop an in situ forming SAIB (sucrose acetate isobutyrate)-PLGA (poly (d, lactide-co-glycolide)) mixture matrix depot for sustained release of risperidone. The factors affecting the risperidone release kinetics were investigated to obtain further insight into the drug release mechanisms. The burst release in vitro was significantly reduced (4.95%) by using DMSO as solvent. And, increasing the PLGA content from 2 to 10% w/w decreased the initial release from 6.95 to 1.05%. The initial release in vivo decreased with increasing PLGA content (2.0% w/w PLGA, C _max = 1161.7 ± 550.2 ng ml⁻¹; 10% w/w PLGA, C _max = 280.3 ± 98.5 ng ml⁻¹). The persistence (AUC_4–20 days) over 20 days increased from 76.8 ± 20.7 to 362.8 ± 75.0 ng d ml⁻¹ by inclusion of 10% PLGA compared with the PLGA-free depot. These results demonstrate that the SAIB–PLGA mixture matrix depot could be useful as a sustained delivery system for risperidone.     

In vitro degradation and cell attachment of a PLGA coated biodegradable Mg–6Zn based alloy

Currently available engineering magnesium alloys have several critical concerns if they are about to be used as biomaterials, particularly the concern about the toxicity of the common alloying elements such as aluminum and rare earth (RE). There is an increasing demand to develop new magnesium alloys that do not contain any toxic elements. It is also desirable, yet challenging, to develop such a material that has a controllable degradation rate in the human fluid environment. This paper presents mechanical properties, degradation, and in vitro cell attachment of a newly developed Mg–6Zn magnesium alloy. The alloy demonstrated comparable mechanical properties with typical engineering magnesium alloys. However, the bare alloy did not show an acceptable corrosion (degradation) rate. Application of a polymeric PLGA or poly(lactide-co-glycolide) coating significantly decreased the degradation rate. The results obtained from cell attachment experiments indicated that the mouse osteoblast-like MC3T3 cells could develop enhanced confluence on and interactions with the coated samples.     

生物医用镁合金表面PLGA涂层研究

镁及镁合金作为可降解吸收生物医用材料的研究已得到关注,但与传统可降解材料相比其腐蚀降解较快,可能导致提前失效.以高纯的Mg-Zn合金为研究材料,采用浸涂提拉法在其表面得到PLGA涂层.结果表明,PLGA涂层致密均匀,耐蚀性好,降解周期长,可以有效保护镁合金在植入初期不发生腐蚀降解,延长其发挥功能的时间,达到良好的医学适用性.     

生物可降解材料PLGA的应力松弛性能

针对基于生物可降解材料聚乳酸-羟基乙酸共聚物(PLGA)的热压成型工艺仿真研究中,粘弹性材料模型参数缺乏的问题,通过单轴拉伸应力松弛试验,研究了生物可降解材料PLGA在5种温度状态下的应力松弛性能。基于时间-温度等效原理,平移得到60℃的松弛模量主曲线,并采用广义Maxwell模型对此主曲线进行拟合。结果表明:随着温度的升高,PLGA材料的松弛时间明显缩短,且拟合曲线与原数据误差较小,说明广义Maxwell模型能较理想地模拟PLGA材料的应力松弛行为。这些数据的获得为后续仿真研究提供了参考。     

可降解高聚物PLGA降解溶蚀的仿真模型

针对可降解高聚物材料聚乳酸和聚乙醇酸的共聚物(PLGA)降解溶蚀的计算机仿真问题,采用蒙特卡罗方法确定聚合物的随机降解寿命的计算表达式,依此建立了PLGA材料降解溶蚀过程的数学模型,并开展溶蚀模型的验证实验,数值仿真与验证实验结果表明,文中的聚合物随机计算寿命值表达式具有更明确的物理意义,所建立的降解溶蚀模型可以直观地反映材料的降解溶蚀过程,材料半衰期之前仿真结果与实验结果一致性较好。该仿真模型能为可降解高聚物材料的功能器件提供一种设计方法。     

PLGA/PCL复合材料的制备及其性能研究

在聚乳酸-羟基乙酸(PLGA)中加入聚ε-己内酯(PCL)、柠檬酸三丁酯(TBC),通过溶液共混制备了PLGA/PCL共混聚合物,通过静电纺膜及涂膜法制备了不同比表面积的降解膜,并对共混材料力学性能和膜的降解性能进行了研究。结果表明:柠檬酸三丁酯作为增容剂对整个共混聚合物的韧性和强度有明显的影响;当聚乳酸-羟基乙酸和聚ε-己内酯的质量比为80/20、增容剂柠檬酸三丁酯的用量为6%时,所得共混聚合物的断裂伸长率达到130%、冲击强度达到9.55kJ·m-2。相同条件下加入聚ε-己内酯(PCL)的膜的降解性能优于单一的聚乳酸-羟基乙酸(PLGA)膜,静电纺丝膜降解性能优于流延法膜。     

Self-assembled nanomicelles using PLGA–PEG amphiphilic block copolymer for insulin delivery: a physicochemical investigation and determination of CMC values

Self-assembled nanomicelles can be used as synthetic biomaterials and colloidal carriers for poorly water-soluble drug delivery systems. Some of these micellar systems have been introduced in clinical trials and showed hopeful results relating to their therapeutic index in patients. Biodegradable nanomicelle was prepared from self-assembling amphiphilic block copolymer composed of poly(dl-lactic-co-glycolic acid) (PLGA) as a core and polyethylene glycol (PEG) as a corona. The PLGA–PEG block copolymer was first synthesized and characterized by FTIR, ¹H NMR, GPC and inherent viscosity measurements. The nanomicelle formed by PLGA–PEG block copolymer in the aqueous solution was characterized by dynamic light scattering, zeta potential, scanning electron microscopy (SEM) and fluorescence excitation and emission spectra of pyrene probe. The critical micelle concentration of obtained nanomicelle was about 0.006 mg/mL, with the size of about 160 nm and the zeta potential of −29 mV. Insulin-loaded PLGA–PEG nanomicelles were prepared by modified dialysis method and the physicochemical parameters of the micelles such as drug content, entrapment efficiency and in vitro drug release were characterized. The results showed that insulin was entrapped into PLGA–PEG nanomicelles with drug loading of 3.9 wt% and entrapment efficiency of 55 wt%. The nanomicelles containing insulin exhibited a controlled release profile. These observations suggested that the PLGA–PEG block copolymers nanomicelles have been prepared by a new synthetic route are potent nanocarrier for poorly water-soluble drugs as insulin.     

骨组织工程PLGA/TCP复合材料的性能研究

骨组织工程的支架要求有与人骨在功能梯度上相一致的材料结构、几何结构和生理功能。PLGA／TCP复合材料具有适用于骨组织工程支架的综合性能。以快速成形技术低温沉积工艺的成形效果来评价材料的成形性能，以体外降解试验来评价材料的降解性能，以国家标准的方法来评价材料的细胞毒性，对PLGA和TCP不同配比下的性能进行了研究，发现TCP含量的增加有利于降低材料的细胞毒性，加快了材料的降解，但同时降低了材料的成形性能。从骨组织工程的临床应用来看，低的细胞毒性是需要首先得到保证的，成形性能则通过其他方式来改善。     

PLGA/HA骨支架材料的降解特性

采用有机泡沫法获得了HA多孔骨架.运用溶胶浇铸法将PLGA溶胶填充入多孔骨架中,制备出骨组织工程用PLGA/HA复合支架材料,并考察了其在模拟体液中的降解性能,通过SEM观察了其表面组织形貌.结果表明,随浆料中HA含量的增加,材料降解后质量损失增大,且随降解时间的延长,PLGA/HA骨支架材料表面粘附的磷灰石相增多,表明该复合材料具有良好的生物活性.     

PLGA改性聚氨酯微球的制备及性能研究

以聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇(PEG)、异佛尔酮二异氰酸酯(IPDI)和2,2-二羟甲基丙酸(DMPA)为原料,采用预聚—扩链—中和—分散法制备PLGA改性聚氨酯水溶液,然后采用钙离子(Ca~(2+))的交联作用凝聚成PLGA改性聚氨酯微球。优化了合成条件,并对PLGA改性聚氨酯微球进行了傅里叶变换红外光谱(FT-IR)和扫描电子显微镜(SEM)表征,研究了PLGA含量和pH对微球降解性能的影响,以盐酸四环素(TH)为模型药物研究微球体外释药情况。结果表明,在降解反应初期微球的降解速率较大,而后趋于平稳,微球在碱性环境降解性能优于酸性环境,载药微球的载药量为0.83%,包封率为59.17%,载药PLGA改性聚氨酯微球的累积释药率可达74%。     

PLGA/TCP材料的浓度-粘度性能研究

为研究骨组织工程材料的成形性能,基于低温沉积制造工艺,研究了PLGA/TCP配制成浆料的浓度、粘度对成形性的影响.首先测定了材料的粘度随浓度的变化关系,然后对不同浓度的材料进行成形,发现材料的粘度对宏观成形效果起着决定性的作用,同时浓度变化使试样的微观结构具有较大差异.因此,可以通过控制浓度即粘度来调整试样的宏观、微观成形效果.     

相分离法制备PLGA微米-纳米多孔结构研究

相分离技术是近年来制备组织工程支架的一项新技术.研究了溶剂、溶液浓度、降温速率对多孔材料微孔结构的影响,确定了获得微米-纳米尺度微结构的参数.通过试验探索出了用高凝固点溶剂低温快速冷冻制备PLGA纳米结构的方法,讨论了溶剂影响微米-纳米多孔结构的因素.通过选取适当的溶剂、冷冻温度和溶液浓度,可以控制获得的多孔结构的尺寸,制备更适合细胞黏附、增殖的组织工程支架.     

冠脉支架表面PLGA涂层制备及其血液相容性研究

采用静电喷涂沉积(electrospray deposition ESD)法在冠脉支架表面制备了PLGA涂层.采用OLYMPUS体式显微镜、原子力显微镜(AFM)观察了涂层宏观表面形貌及三维形貌;通过对涂层支架进行球囊扩张考察了PLGA涂层与支架的结合力;通过血小板粘附实验和动态凝血时间测定研究PLGA涂层的血液相容性.结果表明:ESD法在冠脉支架表面制备PLGA涂层,支架筋拐角处无明显的聚合物胶体缠绕、粘连且涂层表面光滑;PLGA涂层将316L不锈钢基体的微坑覆盖,基体Ra=16.174nm,PLGA涂层Ra=0.149nm,涂层表面粗糙度小;涂层支架撑开后在最大塑性变形位置无涂层撕裂、翘起等缺陷,涂层与支架有良好结合力;PLGA涂层血小板粘附量少,变形小,未引起血小板激活,动态凝血时间长,直到50min未产生凝血,PLGA涂层具有较好的血液相容性.     

PLGA组织工程支架材料在生理盐水中的降解性能

本文利用红外漫反射仪、DSC测试,并通过对PLGA组织工程支架在生理盐水中的失重率、分子量以及生理盐水pH值变化的研究,发现:孔径在200-300微米的PLGA组织工程支架,在37℃,振荡速度为160r/min的生理盐水中,随着降解时间的延长,分子量不断减小;随着降解时间的延长,支架重量有升有降,但长期呈下降的趋势;DSC测试显示,支架材料中的GA链相对于LA链更易降解;FTIR图谱显示,PLGA组织工程支架材料的降解主要是酯键水解。     

PLGA溶胶对多孔HA材料的填充性能研究

采用聚氨酯海绵作为模板,制备出多孔HA中间层.用溶胶浇铸法,将PLGA溶胶填充入多孔HA中间层里,制备出骨组织工程用PLGA/HA复合支架材料.制得的多孔HA中间层孔隙率高(80%～92%),孔径大(500～1000p.m),且有相互连通的孔结构.对PLGA溶胶填充性能的研究结果表明:溶胶粘度影响PLGA溶胶的填充性能,而粘度与浓度、时间、温度和pH值关系密切.当溶胶粘度为50mPa·s时,PLGA胶体的填充性能最好.