鼓室注射治疗梅尼埃病的研究进展

鼓室内药物注射是治疗梅尼埃病眩晕发作的主要方法之一,然而其疗效在个体间存在较大差异,可能与药物进入内耳的效率不同有关。此外,鼓室内注射氨基糖苷类药物会存在感音神经性耳聋的风险。因此,改进鼓室内药物注射方式的药物递送效率和安全性一直是本领域研究的热点。采用新型纳米生物材料构建的药物递送系统显示出较好的应用前景,有望通过单次微量给药,在实现眩晕症状控制的同时降低药物不良反应的发生率。文章综述了两种常用药物,即庆大霉素和地塞米松治疗梅尼埃病的给药方式以及作用机制,为研发用于梅尼埃病治疗的鼓室注射药物新剂型提供参考。

血液透析用小型A浓缩液供液装置设计

为解决只有少数血液透析机使用联机氯化钠,节约使用A浓缩液带来的运输、仓储和劳动强度问题。设计、制造并实验一种小型A浓缩液供液装置,通过混液装置在配液容器中对氯化钠原料及纯化水进行充分搅拌,利用配液容器内部上下分层过滤,获得较为纯净的氯化钠溶液,配合吸液泵、液位检测装置及供液检测装置,使得配置好的氯化钠溶液在混液管中与离子液、纯化水实时进行混合配制成A浓缩液,并进入储液容器中以供血液透析机使用。实验结果表明实现现场自动化配制NaCl溶液,且与A溶液(NaCl除外)和反渗水3种按比例现场配制成1人份A浓缩液,兼具预冲、自动排空、清洗功能。该装置适用于所有能使用桶装A液的血液透析机,节约A液近90%的运输量、运输成本和占地,减轻了女护士提浓缩液的劳动强度问题。

胆碱能抗炎通路在病毒性心肌炎中的抗炎作用及其机制

目的观察切断迷走神经和烟碱治疗对病毒性心肌炎的相关通路蛋白信号传导及转录激活因子3(STAT3)、7-N型乙酰胆碱受体(7-nAChR)和炎症介质的表达变化,探讨胆碱能抗炎通路的作用机制。方法200只雄性BALB/C小鼠随机分为5组:正常对照组、假手术组、烟碱组、迷走神经切断+烟碱组及迷走神经切断组。正常对照组腹腔注射等量0.9%氯化钠注射液,其余4组经腹腔接种CVB3建立急性病毒性心肌炎模型,接种当天记为第0天,第1天开始烟碱组和迷走神经切断组+烟碱组腹腔注射0.4 mg/kg烟碱,余下3组腹腔注射等量0.9%氯化钠注射液,直至第14天末。观察14 d内各实验组随机20只小鼠的生存率,在第7及14天分别从实验组抽取8只小鼠处死,留取心肌组织进行病理组织检查、Western blot及ELISA技术对相关通路蛋白及炎症因子进行检测。结果正常对照组生存率100%,烟碱组生存率高于假手术组,迷走神经切断+烟碱组生存率高于迷走神经切断组(均P <0.05);与假手术组比较,第7及14天,烟碱组心肌病理损伤及炎症减轻,迷走神经切断组心肌病理损伤及炎症加重,与迷走神经切断组比较,迷走神经切断+烟碱组心肌病理损伤及炎症减轻(均P <0.05);第7天,与正常对照组比较各实验处理组p-STAT3表达均升高(均P <0.05),与假手术组比较,烟碱组p-STAT3表达降低,迷走神经切断组表达升高,与迷走神经切断+烟碱组比较,迷走神经切断组表达升高(均P <0.05);在第7及14天,各实验处理组TNF-、INF、IL-1及IL-6等炎症指标均升高,且烟碱组最低,迷走切断组最高。结论烟碱可激动胆碱能抗炎通路减轻小鼠心肌炎症,减少炎症因子表达,而切断迷走神经阻断胆碱能抗炎通路加重小鼠心肌炎症,使炎症因子表达增加;抑制p-STAT3信号蛋白表达可能是胆碱能抗炎通路的作用机制之一。

Injectable chitosan hydrogels loaded with antioxidant agent as first-aid dressings for second-degree burn wounds

Burn wounds are destructive skin traumas typically of irregular shape and large area. Prone to infection, they require frequent dressing replacement, and painless removal of dressings from burn wounds remains a major challenge. This study focuses on the dynamic characteristics and treatment difficulty of burn wounds. Hydrogel dressings based on glycol chitosan and propionaldehyde-or benzaldehyde-terminated 4-arm poly(ethylene glycol) were designed on the basis of Schiff base cross-linking networks. The hydrogels exhibited shape-adaptability, self-healing and fast-degradation properties, which makes these hydrogels suitable for burn wounds. Salvianolic acid B(SaB)-loaded hydrogel exhibited good antioxidant properties in vitro. In a rat model of deep second-degree burn wounds, the SaB-loaded hydrogel could quickly reduce wound temperature, regulate wound oxidant microenvironment, promote angiogenesis, and accelerate wound healing. Thus, the drug-loaded hydrogel shows significant potential as a first-aid dressing for treatment of burn wounds.

中国可降解、可回收高分子材料化学领域发展现状和未来挑战

随着“白色污染”程度的加剧,绿色可持续发展已成为高分子材料领域的时代主题之一。而可降解、可回收高分子材料顺应碳中和、碳减排需求,迎来了全球禁塑政策下广阔的市场机遇。可降解高分子材料通过在主链引入能够断裂的基团,其在保持与传统塑料相当性能的同时,在自然环境下能够自然降解;其中包括以聚乳酸为代表的从生物质来源制造塑料成为了可降解高分子材料的新思路,具有重要的战略意义和社会需求。

“抗肿瘤药物高分子纳米载体的多功能性和协同作用”重大项目结题综述

国家自然科学基金重大项目'抗肿瘤药物高分子载体的多功能性和协同作用'针对当前抗肿瘤纳米药物药效提升受限的关键科学问题,设计新一代高分子药物载体,综合实现抗肿瘤纳米药物的(1)长循环、(2)肿瘤组织富集、(3)肿瘤组织渗透、(4)进入肿瘤细胞、(5)胞内药物释放,提升抗肿瘤纳米药物的总体治疗效果。经过项目组5年(2014—2018年)的努力,在高分子纳米载体结构与体内药物输送特定过程的构效关系、智能响应性高分子纳米药物载体的多功能化研究、复合组装纳米药物载体的功能协同与集成、功能协同化高分子纳米载药系统的疗效和初步安全性评价等方面取得了一系列创新性研究成果。本项目的研究对新一代抗肿瘤纳米药物的发展具有重要意义。

Recent developments in intelligent biomedical polymers

Intelligent polymers or stimuli-responsive polymers may exhibit distinct transitions in physical-chemical properties, including conformation, polarity, phase structure and chemical composition in response to changes in environmental stimuli. Due to their unique 'intelligent' characteristics, stimuli-sensitive polymers have found a wide variety of applications in biomedical and nanotechnological fields. This review focuses on the recent developments in biomedical application of intelligent polymer systems, such as intelligent hydrogel systems, intelligent drug delivery systems and intelligent molecular recognition systems. Also, the possible future directions for the application of these intelligent polymer systems in the biomedical field are presented.

Cytotoxicity of liver targeted drug-loaded alginate nanoparticles

In this study, novel liver targeted doxorubicin (DOX) loaded alginate (ALG) nanoparticles were prepared by CaCl2 crosslinking method. Glycyrrhetinic acid (GA, a liver targeted molecule) modified alginate (GA-ALG) was synthesized in a heterogeneous system, and the structure of GA-ALG and the substitu-tion degree of GA were analyzed by 1H NMR, FT-IR and elemental analysis. The drug release profile under the simulated physiological condition and cytotoxicity experiments of drug-loaded GA-ALG nanoparticles were carried out in vitro. Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that drug-loaded GA-ALG nanoparticles have spherical shape structure with the mean hydrodynamic diameter around 214 ± 11 nm. The drug release was shown to last 20 days, and the MTT assay suggested that drug-loaded GA-ALG nanoparticles had a distinct kill-ing effect on 7703 hepatocellular carcinoma cells.

Glycyrrhetinic acid-modified nanoparticles for drug delivery: Preparation and characterization

In this work, glycyrrhetinic acid-modified chitosan (mGA-suc-CTS) used as liver targeted carrier for drug delivery, was prepared via hemisuccinate as a bridged group. The structure of the product was confirmed by IR and NMR methods and the degree of substitution (DS) of glycyrrhetinic acid groups was estimated via elemental analysis. Nanoparticles were formed by ionic gelation methold. The drug-loading and release behavior of the nanoparticles were investigated using BSA as the model drug. The results indicated that the carrier with a highest DS of 5.19% could be got and the DS was controlled by changing reaction temperature or feed ratio. BSA could be entrapped into the nanoparticles with the drug-loading ratio of 26.3% and the encapsulation efficiency of 81.5%. A sustained release over an 11-day period was observed in pH 7.4 in vitro.

Co-delivery of doxorubicin and paclitaxel with linear-dendritic block copolymer for enhanced anti-cancer efficacy

A series of well-defined amphiphilic linear-dendritic block copolymers(telodendrimers, MPEG-b-PAMAM-cholesterol) with 1,2,4 or 8 cholesteryl groups(named as P1, P2, P4, P8, respectively) were synthesized. Their chemical structures were characterized with 1H NMR and mass spectrum(MALDI-TOF MS). The telodendrimers could self-assemble into micelles in aqueous solution, and encapsulate chemotherapeutic drug doxorubicin(DOX) and paclitaxel(PTX) for combination therapy. All the telodendrimers could encapsulate DOX with similar capability. However, their drug-loading capability of PTX is increased with the increasing number of cholesteryl groups. P8 exhibited much higher PTX loading efficiency than its counterparts. Thus, P8 was selected for further application of drug delivery in the paper. The drug-loading micellar nanoparticles(NPs) of P8 were spherical in shape and their diameters were less than 150 nm which were determined by dynamic light scattering measurements(DLS) and transmission electron microscope(TEM). In vitro drug release experiment demonstrated that P8 exhibited a controlled release manner for both DOX and PTX, and the two drugs were released simultaneously. In vitro cytotoxicity experiment further demonstrated that the co-delivery of DOX and PTX in P8 exhibited better anti-cancer efficiency than the delivery systems encapsulated with single drug(DOX or PTX). This indicates a synergistic effect. The co-delivery system showed potential in future anti-cancer treatment.

Mechanical and thermal properties of polypeptide modified hydroxyapatite/poly(L-lactide) nanocomposites

A new type of polypeptide(poly(-benzyl-L-glutamate)(PBLG))modified hydroxyapatite(HA)/poly(L-lactide)(PLLA)nanocomposites(PBLG-g-HA/PLLA)were prepared by the solvent-mixing method,and their mechanical and thermal properties were investigated.The tensile test showed that the mechanical properties of PBLG-g-HA/PLLA nanocomposites were better than that of PLLA,even a 0.3 wt%content of PBLG-g-HA in the nanocomposites could make the tensile strength 12%higher than that of the neat PLLA sample,and the tensile modulus was about 17%higher than that of the PLLA sample.The thermal gravimetric analysis(TGA)showed that the PBLG-g-HA/PLLA composites have better thermal stability than the PLLA sample.The differential scanning calorimetry(DSC)was used to characterize the effect of PBLG-g-HA on the crystallization of PLLA.The isothermal crystallization behavior showed that the half crystallization time(t1/2)of PBLG-g-HA/PLLA was much shorter than that of the PLLA sample.When the PBLG-g-HA content was 10%,t1/2 was only 18.7 min,while t1/2 of the PLLA sample was 61.4 min.The results showed that the PBLG-g-HA worked as a nucleating agent and enhanced the crystallization speed of PLLA.

PLLA-PCys co-electrospun fibers for capture and elution of glutathione S-transferase

The copolymer poly(L-lactic acid)-b-poly(L-cysteine) (PLA-b-PCys) was co-electrospun with PLGA into ultrafine fibers. The reduced glutathione (GSH) was conjugated to the fiber surfaces via disulfide bonds. The glutathione S-transferase (GST) was captured onto the GSH fibers via specific substrate-enzyme interaction between the bound GSH and GST. The captured GST was eluted with free GSH aqueous solution and lyophilized to get pure GST powders. The results show that the GSH moieties on the fiber surface retain the bioactivity of the free GSH and thus they can bind specifically with GST and the GST in solution is captured onto the fiber surface. In addition, the bound GSH is not as active as free GSH so that the captured GST can be eluted off from the fiber by free GSH aqueous solution. Based on this principle, GST itself or its fused proteins can be separated and purified very easily. The preliminary purification efficiency is 6.5 mg·(gPCys)-1. Further improvements are undertaken.

Biocompatible in situ-forming glycopolypeptide hydrogels

A lack of biological activity hinders the application of synthetic hydrogels in tissue engineering and regenerative medicine.However,the use of glycopolypeptides in hydrogel synthesis may provide the materials with the desired biological activities.Herein,we prepared three in situ-forming hydrogels from various phenol-functionalized glycopolypeptides.The gelation time,mechanical properties,degradation properties,and biocompatibility of the hydrogels were assessed.Gelation time ranged from 11 to 380s,depending on the concentration of horseradish peroxidase.The galactose-modified polypeptide hydrogel showed the highest storage modulus with an obvious stress relaxation phenomenon.The prepared hydrogels exhibited good degradation properties and compatibility to cells and tissues.Furthermore,the rate of immune cell accumulation around the mannosemodified polypeptide hydrogel was the fastest among the hydrogels.

Recent advances in organic and polymeric carriers for local tumor chemo-immunotherapy

Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regimen is chemotherapy combined with focused immunotherapy.This is implemented to induce the apoptosis of tumor cells and can activate immune responses,improving the clearance rate of primary lesions and maintaining the resistance to postoperative tumor recurrence and metastasis.Advances in micro/nanotechnology,nanomedicine and biomaterials have contributed to the development of enhanced local drug co-delivery systems for cancer treatment,improving tumor targeting and ameliorating severe systemic complications.Carrier materials can achieve the local long-term controllable release of multiple drugs,which not only avoids rapid drug diffusion from the pathological site,but can achieve synergistic effects at lower drug concentrations.Polymeric carriers display excellent biocompatibility and biodegradability;especially,some of them also have anti-tumor effects.The aim of this article was to review recent progress in the use of organic and polymeric materials for local tumor chemo-immunotherapy,which can be used as carriers for chemotherapeutic drugs,immune adjuvants and genes,including amphiphilic nanoparticles,nanocapsules,nano-disks,nano-polyplex particles,hydrogels and implantable materials.

Influence of residual chirality on the conformation and enzymatic degradation of glycopolypeptide based biomaterials

Glycopolypeptides as analogs of glycoproteins or glycosaminoglycans represent attractive building blocks for the construction of biomimetic biomaterials.However,the effects of amino acid chirality on the conformation and enzymatic degradation of glycopolypeptides are often overlooked.Here,we synthesized and characterized a range of glycopolypeptides composed of galactosylated poly(γ-propargylglutamate)s containing L-and/or D-glutamate residues.Glycopolypeptides containing pure Lglutamate residues were predominantlyα-helical,and the helicity increased over the degree of polymerization of the polypeptide backbones(24 to 44).The glycopolypeptide with pure D-glutamate residues adopted a mirroredα-helical conformation,whilst apparent random coil conformation was observed for the glycopolypeptide with equally mixed enantiomeric residues.The enzymatic degradation rates of the glycopolypeptides were markedly reduced following the introduction of D-glutamate residues into backbones.Galactoside pendants on these glycopolypeptides maintained their binding to peanut agglutinin.These structureproperty relationships provide new insight for the design of biomimetic biomaterials containing glycopolypeptides.

The synthesis, deprotection and properties of poly(γ-benzyl-L-glutamate)

With dicy- clohexylamine as initiator, the influence of monomer concentration, and reaction temperature and time on the polymerization of BLG NCA was examined. Three reagents were used for the deprotection of benzyl groups in PBLG, including hydrobromic acid/acetic acid (33 wt.%), NaOH aqueous solution and trimethylsilyl iodide (TMSI). Through examining the molecular weight of PLGA obtained using different deprotection methods, it was revealed that TMSI could minimize chain cleavage in the process of deprotection and retain the degree of polymerization. The biocompatibilities of PBLG obtained using different initiators were evaluated by a live/dead assay against L929 fibroblast cells. The in vitro cytotoxicities of PLGA obtained using different deprotecting agents were evaluated by a methyl thiazolyl tetrazolium assay. The results revealed that both PBLG and PLGA exhibited good biocompatibilities.

Matrix metalloproteinase-sensitive poly(ethylene glycol)/peptide hydrogels as an interactive platform conducive to cell proliferation during 3D cell culture

The response of extracellular matrix(ECM) to dynamic cell signals is of great significance for the regulation of cell behavior. In the present study, we prepared a type of matrix metalloproteinase(MMP)-sensitive degradable hydrogels(MSDHs) via the catalyst-free o-phthalaldehyde(OPA)/amine cross-linking reaction between o-phthalaldehyde-grafted four-arm poly(ethylene glycol)(4aPEG-OPA) and an MMP-sensitive degradable peptide. The gelation rates and storage moduli of MSDHs and the MMP-insensitive hydrogels(MIHs) based on an MMP-insensitive scramble peptide were comparable and dependent on the concentrations of precursor polymers. MSDHs were degradable while MIHs were stable in the presence of proteinase in vitro.The degradation of MSDHs was obviously faster than that of MIHs after subcutaneous injection into rats. In addition, both types of poly(ethylene glycol)/peptide hydrogels displayed excellent cytocompatibility in vitro, and showed good histocompatibility in vivo in the subcutaneous layer of rats. Furthermore, the proliferation of several MMP-expressing cell lines including MDA-MB-231 cells within MSDHs was obviously faster than that in MIHs, indicating the influence of metabolism-mediated scaffold degradation on the cell proliferation. This study provides a new biocompatible and biodegradable 3 D cell culture interactive platform for regulation of cell behavior.

Surface Modification of 316L Stainless Steel by Grafting Methoxy Poly（ethylene glycol） to Improve the Biocompatibility

Percutaneous coronary intervention（PCI） has become an important method for the treatment of the pa- tients with coronary heart disease; however, problems, such as vascular endothelial inflammation, late thrombosis, and stent restenosis still exist as a result of poor biocompatibility of the materials. To enhance the biocompatibility, methoxy poly（ethylene glycol）（mPEG） was immobilized on the surface of AISI 316 grade stainless steel（SS）（AISI： American Iron and Steel Institute）. First, silanized mPEG was synthesized by the direct coupling of mPEG with 3-isocyanatopropyltriethoxysilane（IPTS） via urethane bonds, and the silanized mPEG was then grafted on the surface of SS that was hydroxylated with piranha solution. The results obtained from contact angle goniometry, X-ray pho- toelectron spectroscopy（XPS）, and atomic force microscopy（AFM） confirm that the mPEG modified steel contained more C and Si and less Fe and Cr on its surface, exhibiting a morphological change and decrease in the contact angle. The biocompatibility of the mPEG modified SS was evaluated with fibrinogen adsorption, platelet activation and adhesion, and human umbilical vein endothelial celI（HUVEC） adhesion. Fibrinogen adsorption, platelet activation, and adhesion were clearly suppressed on the surface-modified steel. In addition, human umbilical vein endothelial cell（HUVEC） could adhere and proliferate on the surface of the mPEG-modified SS. This study indicates that the modification of 316L SS with mPEG could enhance the biocompatibility and provide a primary experimental founda- tion for the development of next-generation coronary stent materials for clinical application.

Synthesis of PEGylated Salicylaldehyde Azine via Metal-free Click Chemistry for Cellular Imaging Application

Ill tliis work, two kinds of PEGylated salicylaldehyde azine(SA) polymers were prepared and investigated for cellular imaging applications. First, a diazido derivative of SA was synthesized and subsequently PEGylated with polyethylene glycol monomethyl ether(mPEG) by metal-free azide-alkyne 1,3-dipolar cycloaddition reaction. The formed triazole group in niPEG-SA was then converted into cationic triazolium group by N-alkylation reaction. Botli the synthesized polymers, niPEG-SA and N-alkylated niPEG-SA, showed good dispersibility in water, but differences in self-assembly of nanostructures. The niPEG-SA with triazole groups self-assembled into micelles, while the N-alkylated mPEG-SA with triazolium groups sell-assembled into vesicles. Furthemiore, mPEG-SA and N-alkylated niPEG?SA naiioparticles showed bright fluorescence due to the aggregation of AIE-active SA molecules in the nanoparticles and could be successfully used as fluorescent naiioprobes for bioimaging applications in HeLa cancer cells. Finally, both the synthesized polymers showed minimal cytotoxicity and low hemolytic activity. Therefore, these PEGylated SA polymers proved to be promising bioimaging nanoprobes or traceable dnig delivery vehicles.

Poly（L-lactide）-grafted Bioglass/Poly（lactide-co-glycolide） Scaffolds with Supercritical CO2 Foaming Reprocessing for Bone Tissue Engineering

The bioglass particles/poly（lactide-co-glycolide）（BG/PLGA） scaffold has been extensively explored for biomedical applications due to its excellent advantages of mechanical property and controllable degradation rate. In ottr previous studies, the BG nanoparticle sttrface-grafted with poly（L-lactide）（PLLA） could substantially improve the phase compatibility between the polymer matrix and the inorganic phase and the biocompatibility of the scaffolds. However, using the traditional preparation methods to prepare the composite scaffold can barely achieve a high po- rosity and porous connectivity. In this work, the PLLA-grafted bioglass/PLGA（g-BG/PLGA） scaffolds were prepared by supercritical carbon dioxide foaming（Sc-CO2） with before or after particulate leaching（PL） method（Sc-CO2-PL or PL-Sc-CO2 method, PL/Sc-CO2 methods） and their applications in bone replacement and tissue engineering were investigated. The porosities of the g-BG/PLGA scaffolds prepared by the PL/Sc-CO2 methods were higher than 90%, and their mechanical properties had similar values with human cancellous bone. The proliferations of osteoblasts on the scaffolds were dependent on different preparation methods. The PL/Sc-CO2 methods significantly increased the proliferations of the cells. Computed tomography（CT） three-dimensional（3D） reconstruction tomographies of the implantation study for repairing calvarium defects of rabbits demonstrated that the calvarium defects were almost completely filled by the osteotylus in PL/Sc-CO2 method group at 12 week post-surgery, while there was little callus formation in PL method group and untreated control group. These results indicate that the g-BG/PLGA scaffolds prepared by the PL/Sc-CO2 methods exhibit rapid mineralization and osteoconductivity and are the optimal composites for bone repair.