可降解抗生素缓释载体治疗慢性骨髓炎动物模型的实验研究

目的通过动物模型实验研究可降解缓释抗生素载体对慢性骨髓炎的治疗效果。方法40只新西兰大白兔通过葡萄球菌接种经4周时问演变成为慢性股骨骨髓炎模型,随机分为4组,每组10只。A组病灶植入万古霉素一明胶海绵;B组植入万古霉素一硫酸钙;C组病灶内植人万古霉素一纳米羟基磷灰石,D组单纯植入万古霉素粉剂0．1g,分别于术后5d,15d及30d测量病灶分泌物抗生素药物浓度,同时取病灶局部病理检查进行分析比较。结果术后30d取病灶组织,B组及c组20只白兔有18例术后30d病理切片白细胞数明显减少,并有明显的新生肉芽组织q三成,而A组及D组20只白兔术前及术后对照白细胞数量未见明显减少。病灶引流液药物浓度A组及D组数据均呈现在植入后爆发性释放,很快便急剧下降,失去治疗作用。B组及c组引流液药物浓度呈现缓慢持续且有效的释放规律,至术后30d均值仍高于最低有效浓度。结论可降解缓释抗生素载体对慢性骨髓炎治疗有效,各种载药体具有不同的生物学特性,值得进一步深入研究探讨。     

Fully biodegradable septal defect occluder—A double umbrella design

Current percutaneous devices for septal defect treatment are made of nondegradable metallic and synthetic fabric materials. These devices are not ideal due to risks of future complications from device erosions and potential obstructed access for future transseptal procedures. The biodegradable double umbrella device was made of fully biodegradable polymers, featured with two discs connected with a stretchable stem. The devices were inserted across the PFO model created on Yorkshire swines through a short sheath by open thoracotomy. Fluoroscopic imaging and echocardiography obtained during the 1‐month follow‐up study period showed that the devices were in stable position with no shunt. The in‐vitro degradation study and post‐mortem explantation confirmed that the devices have good integrity and mechanical strength during the 1‐month trial. Furthermore, the devices appeared to be well endothelialized after 1 month. These results showed clearly that it is feasible to replace the current nondegradable devices with the new generation biodegradable PFO occluders. This work studied and proved the feasibility of interventional closure of patent foramen ovale (PFO) with a fully biodegradable device, that we call the “double umbrella” (DU) for its symbolic design. © 2010 Wiley‐Liss, Inc.     

Pharmacokinetics of Intra-Arterial Mitomycin C With or Without Degradable Starch Microspheres (DSM) in the Treatment of Non-Resectable Liver Cancer

The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marrow toxicity were studied in a phase II multicenter study. Sixty-three patients with nonresectable primary or secondary liver cancer were randomized to receive either i.a. mitomycin C 15 mg/m² first, followed 5 weeks later by mitomycin C 15 mg/m² plus DSM 360 mg administered into the hepatic artery (group I) or the same treatments in the opposite sequence (group II). In 36 out of 47 patients who received at least 2 treatments, peripheral venous blood samples were analyzed for mitomycin C pharmacokinetics on a minimum of 2 paired courses. In all patients, the area under the concentration time curve (AUC) was significantly lower when the drug was co-administrated with DSM, but the terminal half-life (t_1/2) of mitomycin C was unchanged. In group I the addition of DSM resulted in a significantly lowered AUC, but not in group II. The discrepancy between the 2 groups is probably due to differences in DSM-induced intra-hepatic shunting. The addition of DSM resulted in significantly higher platelet nadir values, but unchanged white blood cell count nadir value. In conclusion, DSM reduce the systemic exposure of mitomycin C and seem to lessen the haematologic toxicity judged from a less pronounced decrease in platelets.     

Adenovirus vector-mediated gene transfer using degradable starch microspheres for hepatocellular carcinoma in rats

BACKGROUND: When gene therapy is performed for malignant tumors, gene transfer efficiency and selectivity are extremely important. The delivery of anticancer agents and embolic agents through tumor feeding artery is known as transarterial embolization. We speculated that genes might be efficiently and selectively transferred to hepatocellular carcinomas (HCCs) by degradable starch microspheres (DSM) as the embolic agent, which could be trapped within the tumor and release a gene vector. Therefore, we studied the use of DSM for adenovirus vector-mediated gene transfer to HCC in vivo. MATERIAL AND METHODS: HCC was induced in rats with diethylnitrosamine and phenobarbital, after which either AxCALacZ and DSM or AxCALacZ alone was injected through the hepatic artery. RESULTS: Histological examination revealed that beta-galactosidase expression was greater (P < 0.001), and more selective (P < 0.001) in tumors after injection of AxCALacZ and DSM, than after injection of the vector alone. CONCLUSION: Injection of DSM together with an adenovirus vector through the hepatic artery can result in efficient and cancer-selective transfer of genes to HCC.     

Intra-articular fate of degradable poly(ethyleneglycol)-hydrogel microspheres as carriers for sustained drug delivery

A novel degradable microsphere (MS) for intra-articular drug delivery, composed of a polyethylene glycol (PEG) core containing degradable regions made of short poly-(lactic-co-glycolic acid) (PLGA) sequences – named PEG-hydrogel MS – was injected into the cavity of sheep shoulder joint, and compared to non-degradable MS devoid of hydrolysable crosslinker in terms of location, degradation and inflammation. One week after intra-articular injection both groups of MS were localized beneath the synovial lining of the synovial fringes located at bottom of the shoulder joint, while a fraction of particles remained in synovial fluid. Histological analyses made one and 4 weeks after intra-articular injection showed cell proliferation around the non-degradable MS entrapped within the synovium. By contrast, degradable PEG-hydrogel MS were surrounded by few cells. The degradation of degradable PEG-hydrogel MS within the synovium was slow and was not fully complete after four weeks. Our findings indicate that the tissue entrapment of MS below the synovial lining was independent of the material degradability, while degradable PEG-hydrogel MS are less inflammatory than the non-degradable one. Degradable PEG-hydrogel MS offer several advantages over the non-degradable MS as carriers for a sustained drug delivery in synovial tissue according to the low intensity of inflammatory reaction triggered in synovium.     

Transfection of primary human nasal epithelial cells using a biodegradable poly (ester amine) based on polycaprolactone and polyethylenimine as a gene carrier

The purpose of this study was to prepare and characterize poly (ester amine) (PEA)/pGL3 complexes and investigate their transfection efficiency in human nasal epithelial (HNE) cells. Particle size, zeta potential, and gel retardation characteristics of PEA /pGL3 complexes were also measured. After treatment of DNase-I, protection and release assay of PEA/pGL3 complexes were performed. To assess the transfection efficiency and cytotoxicity, measurement of relative luciferase activity and MTS assay were performed. PEA/pGL3 complexes showed effective and stable DNA condensation with the particle sizes below 200 nm, implicating their potential for intracellular delivery. PEA/pGL3 complexes successfully transfected into the HNE cells with higher viability of the cells. These results suggested that, the PEA can be used as an efficient cationic polymeric vehicle which provides a versatile platform for further investigation of structure property relationship along with the controlled degradation, significant low cytotoxicity, and high transfection efficiency of the primary HNE cells.     

Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems

Importance of the field: The advancement in material design and engineering has led to the rapid development of new materials with increasing complexity and functions. Both non-degradable and degradable polymers have found wide applications in the controlled delivery field. Studies on drug release kinetics provide important information into the function of material systems. To elucidate the detailed transport mechanism and the structure-function relationship of a material system, it is critical to bridge the gap between the macroscopic data and the transport behavior at the molecular level.

Areas covered in this review: The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literature published after the 1990s. The release kinetics of selected drug compounds from various material systems is discussed in case studies. Recent progress in the mathematical models based on different transport mechanisms is highlighted.

What the reader will gain: This article aims to provide an overview of structure-function relationships of selected non-degradable and degradable polymers as drug delivery matrices.

Take home message: Understanding the structure-function relationship of the material system is key to the successful design of a delivery system for a particular application. Moreover, developing complex polymeric matrices requires more robust mathematical models to elucidate the solute transport mechanisms.     

应用可降解腔内支架的无缝合吻合术在狗胆肠吻合模型的实验研究

目的 传统的手工缝合行胆肠吻合术操作困难、费时,尤其在小胆管吻合和腹腔镜手术时明显。为简化和改良手术操作,我们设计了一种新的应用可降解腔内支架的无缝合胆肠吻合术。本文拟在狗胆总管十二指肠吻合模型中评估该无缝合方法的可行性和安全性。方法 为无缝合胆总管十二指肠吻合术设计一种腔内吻合支架管,这种专利支架管直径3mm和4mm,材料为可降解聚乳酸。38条毕格犬随机分为支架组（SG n=20）和对照组（CG n=18）。SG组应用无缝合支架法行胆总管十二指肠端侧吻合,CG组行传统可吸收缝线间断一层胆总管十二指肠端侧吻合。动物分术后1、3、6、12月4个亚组,比较两组术中吻合手术时间、术中吻合口耐受压、胆漏发生率、术后吻合口爆破压差异,观察两组术后胆红素和肝酶变化、术后1,3,6,12月取材的吻合口组织病理形态学改变,包括HE染色和Masson染色,比较两组吻合口羟脯氨酸含量,观察两组吻合口疤痕纤维组织增生状况。MRCP了解术后6月,12月两组吻合口状况。结果 手术均顺利完成,支架组吻合时间明显小于对照组(SG19.2±4.3min VS CG29.2±7.1min, P 0.000);两组各有1例胆漏并死亡（SG5.0% VS CG 5.6%,P=0.695)。两组间术中吻合口耐受压、术后胆漏发生率、术后各时期吻合口爆破压、吻合口羟脯氨酸含量、胆红素和肝酶测定均无显著性差异。MRCP检查及病理检查未发现吻合口狭窄和梗阻。结论 在狗胆总管十二指肠吻合模型中,无缝合腔内可降解支架胆吻合方法具有可行性和安全性。     

聚内消旋乳酸椎间融合器的生物力学测试

目的 研制用聚内消旋乳酸(PDLLA)制成椎间融合器,通过动物实验,考察其生物力学变化情况,为进一步加以改进和临床应用提供动物实验的基础.方法 通过光镜观察椎间植骨融合情况.通过生物力学测试,检测脊柱融合的不同阶段,使用可降解椎间融合器引起的椎间融合的生物力学变化.结果 椎间植骨融合良好.材料本身的力学强度高于骨组织,因此,早期的力学结果显示其抗压、抗扭强度均明显高于对照组.后期随着材料的降解,其力学特性也随之改变,逐渐与对照组结果相近.结论 材料对植骨融合无负面影响.PDLLA材料在椎间植骨融合过程中,可提供足够的力学强度.保证植骨部位的融合,避免塌陷.     

In Vitro and In Vivo Biocompatibility of Novel Zwitterionic Poly(Beta Amino)Ester Hydrogels Based on Diacrylate and Glycine for Site‐Specific Controlled Drug Release

New (β‐aminoester) hydrogels (PBAE) based on di(ethylene glycol)diacrylate and glycine are successfully synthesized and characterized for the first time in this work. PBAE macromers are obtained using Michael addition. By changing the diacrylate/amine stoichiometric ratio, but maintaining it >1, samples with different chemical structure containing acrylate end‐groups are obtained. The hydrogels are synthesized from macromers utilizing free radical polymerization. Chemical structure of macromers and hydrogels is confirmed by proton nuclear magnetic resonance, and Fourier transform infra‐red spectroscopy. Swelling and degradation rates in physiological pH range change notably with pH and monomer molar ratio, validating pH sensitivity and zwitterionic behavior, which can be finely tuned by changing any of these parameters. In vitro cytotoxicity and in vivo acute embryotoxicity in zebrafish (Danio rerio) performed to assess the biocompatibility of the novel hydrogel materials and their degradation products reveal that materials are nontoxic and biocompatible. The Cephalexin in vitro drug release study, at pH values 2.20, 5.50, and 7.40, demonstrates pH‐sensitive delivery with the release profiles effectively controlled by pH and the hydrogel composition. PBAE hydrogels exhibit great potential for a variety of biomedical applications, including tissue regeneration and intelligent drug delivery systems.