A Pilot First-in-Human Study of Embrace,a Polyethylene Glycol-Based Liquid Embolic Agent,in the Embolization of Malignant and Benign Hypervascular Tumors

PurposeTo investigate the safety and efficacy of an aqueous polyethylene glycol-based liquid embolic agent, Embrace Hydrogel Embolic System (HES), in the treatment of benign and malignant hypervascular tumors.Materials and MethodsA prospective, single-arm, multicenter study included 8 patients, 5 males and 3 females, with a median age of 58.5 years (30–85 years), who underwent embolization in 8 tumors between October 2019 and May 2020. Technical success was defined as successful delivery of HES to the index vessel, with disappearance of >90% of the targeted vascular enhancement or, for portal vein embolization, occlusion of the portal branches to the liver segments for future resection. The volume of HES administered, ease of use (5 point Likert scale), administration time, and adverse events (AEs) were recorded. Evaluation was performed at 7, 30, and 90 days via clinical assessment and blood testing, and follow-up imaging was performed at 30 days.ResultsEight patients were enrolled, and 10 embolizations were performed in 8 lesions. Tumors included hepatocellular carcinoma (n = 4), renal angiomyolipoma (n = 3), and intrahepatic cholangiocarcinoma (n = 1). Technical success was 100%, and the average ease of use was 3.3 ± 1.0 SD. The HES delivery time was 1–28 minutes (median, 16.5 minutes), and the HES volume injected was 0.4–4.0 mL (median, 1.3 mL). All patients reached 30-day follow-up with imaging, and 6 patients reached 90-day follow-up. There were 3 serious AEs in 2 patients that were unrelated to the embolic agent.ConclusionHES resulted in a 100% embolization technical success rate. The product ease of use was acceptable, and no target vessel recanalization was noted on follow-up imaging at 30 days.     

Survivorship Comparisons of Ultracongruent,Cruciate-Retaining and Posterior-Stabilized Tibial Inserts Using a Single Knee System Design: Results From the Australian Orthopedic Association National Joint Replacement Registry

BackgroundUltracongruent (UC) tibial inserts can increase knee replacement stability, but how survivorship compares to cruciate retaining (CR) or posterior stabilized (PS) inserts is unclear.MethodsData from a large joint registry were used to calculate the cumulative percent revision of a single popular knee design used with different inserts. There were 67,523 procedures, of which 12,434 were UC, 21,635 CR, and 33,454 PS. Revision rates and reasons for revision were analyzed.ResultsThe cumulative percent revision at 18 years was 8.3% for UC, 9.2% for CR, and 8.9% for PS. There was no difference when UC was compared to CR, but PS had a higher risk of revision. Revision reasons were similar.ConclusionCompared to the CR, an UC insert did not increase revision rates and was actually lower than a PS insert. An UC insert does not compromise long-term total knee arthroplasty survivorship in the Genesis II prosthesis.     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Vertical interpositional augmentation genioplasty with porous polyethylene

Recent advances in the field of biomatrix porous implant technology has stirred the interest of the oral and maxillofacial surgical community. One such material (Medpor), is a biocompatible, large-pore, high-density polyethylene implant which has proven both experimentally and clinically to fulfil the criterion for maxillofacial reconstructive and aesthetic surgical grafting.     

Cosolvency of Dimethyl Isosorbide for Steroid Solubility

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI–PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.     

软骨细胞诱导骨髓基质干细胞构建带内支撑的组织工程化软骨

目的 探讨以聚羟基乙酸(PGA)包裹特定形态的医用假体材料--多孔高密度聚乙烯(HDPE,商品名为MEDPOR)为支架,应用软骨细胞诱导骨髓基质干细胞(BMSCs),共培养构建特定形态的带内支撑组织工程化软骨医用假体的可能性.方法 以直径3 mm、长5 mm的圆柱形HDPE,外裹 1 mm厚PGA为支架,将体外分别培养的新生猪BMSCs和耳郭软骨细胞按7∶3混合,以10×10 7/ml细胞浓度接种于支架上,同时以相同浓度的单纯软骨细胞和单纯BMSCs分别接种,作为阳性对照组(PC组)和阴性对照组(NC组).经体外培养2周及在裸鼠皮下移植4、8周后取材 ,行大体观察、组织学、组织化学及免疫组化检测.结果 各组细胞均与材料黏附良好.实验组和阳性对照组均形成了大体形态良好的HDPE-软骨复合体,内支撑的HDPE与外层软骨结合紧密.组织学可见成熟的软骨陷窝结构,软骨渗入HDPE孔隙内部、异染基质及Ⅱ型胶原呈强阳性表达.结论 以HDPE为内支撑,外裹PGA的支架,接种混合细胞,可于皮下构建特定形态、组织学良好的HDPE-软骨复合体.     

橡胶木粉填充LLDPE复合材料的结构和力学性能

用橡胶木粉填充线性低密度聚乙烯(LLDPE)，研究了酸、碱溶液预处理木粉的效果和硅烷偶联荆(KH-570)、MMA接枝的天然橡胶胶乳(MGL-30)两种改性剂对橡胶木粉表面改性的效果，以及未粉粒径和填充量等对木粉／LLDPE复合材料力学性能的影响，并用SEM对复合材料拉伸断面的形态结构进行了分析。结果表明：木粉的拉径、木粉填充量和改性荆用量对复合材料的力学性能有较大的影响，经碱溶液预处理再用改性荆改性后的木粉能有效地改善木粉与LLDPE的界面粘结强度，提高橡胶木粉／LLDPE复合材料的力学性能。     

聚乙烯颗粒对人单核细胞分泌促炎因子与抗炎因子的影响

[目的]探讨聚乙烯颗粒对人单核细胞分泌促炎因子与抗炎因子的影响.[方法]用Ceridust 3615 颗粒(聚乙烯颗粒)(平均直径14.27,6.39,1.74,1.01,0.54和0.28 μm)分别刺激人单核细胞,颗粒体积与细胞数的比例为100:1和10:1.在颗粒刺激细胞24 h后,运用ELISA检测培养上清液中的促炎因子(白介素-1β,白介素-6和细胞坏死因子α)及抗炎因子(白介素-10)的表达.[结果]Ceridust 3615 颗粒可刺激单核细胞分泌白介素-1β(IL-1β)、白介素-6(IL-6)和细胞坏死因子α(TNFα),但未能引起白介素-10(IL-10)的表达.颗粒比例增高可促使单核细胞分泌更多的IL-6和TNFα,却减少IL-1β分泌,对IL-10的分泌则无影响.个体差异使巨噬细胞对同种颗粒的刺激产生不同的反应,其差异可达到30倍.[结论]个体差异是影响人工关节寿命的重要因素,聚乙烯颗粒可刺激单核细胞产生炎因子但对产生抗炎因子(IL-10)的作用不明显,提示促炎因子与抗炎因子的不平衡或许是人工关节松动不断进展的另一重要因素.     

Use of an in Vitro Model for the Assessment of Muscle Damage from Intramuscular Injections: in Vitro-in Vivo Correlation and Predictability with Mixed Solvent Systems

The potential of binary mixtures of propylene glycol–water, ethanol–water, and polyethylene glycol 400–water to cause skeletal muscle damage (myotoxicity) following intramuscular injection was examined with an in vitro model using the isolated rat muscle. At moderate concentrations (20–40%, v/v) of the organic cosolvent, the order of myotoxicity was propylene glycol > ethanol polyethylene glycol 400. The in vitro results were then compared with in vivo toxicity in rabbits after injection of normal saline, 40% (v/v) polyethylene glycol 400, 40% (v/v) propylene glycol, indocyanine green in normal saline, and indocyanine green in 40% (v/v) propylene glycol. Employing the area under the creatine kinase activity curve from 0 to 72 hr as the index of skeletal muscle damage, an excellent in vitro–in vivo correlation was observed. The basic myotoxicity relationships obtained from the binary cosolvent systems were then used to examine the myotoxicity of ternary organic cosolvent mixtures. Several mixed solvent systems with the same theoretical molar solubilization power for a model compound, diazepam, were selected to determine (1) if myotoxicity can be reduced by changing the composition of the ternary mixtures and (2) if myotoxicity of the individual components is additive. For the solvent systems containing propylene glycol, ethanol, and water, the total myotoxicity equaled the sum of the individual myotoxicity of each component. In contrast, for the solvent systems containing polyethylene glycol 400, the total myotoxicity was only half of the sum of individual toxicities. These results suggest that polyethylene glycol 400 in mixed cosolvent systems might have a protective effect on the myotoxicity generated by intramuscular injections.     

Polyethylenes Having Well‐Defined Bimodal Molecular Weight Distributions Formed with Bis(phenoxy‐imine) Zr Complexes

Summary: Bis(phenoxy‐imine) Zr complexes with MAO activation can produce polyethylenes with well‐defined bimodal molecular weight distributions. Polymerization behavior indicates that minor changes in the ligand structures can have a significant effect on the modality of the resulting polyethylenes. Although there is no direct relationship between the bimodal catalytic behavior and the structure of a precatalyst complex in solution, a precatalyst complex having a methyl or methoxy group para to the phenoxy‐oxygen inclined to exhibit bimodal behavior whereas that with a pentafluorophenyl group on the imine‐nitrogen displayed unimodal behavior. Polymerization results suggest that bimodal behavior is linked to the presence of two kinds of cationic active species, which arise from different modes of ligand coordination. A qualitative correlation was found between the calculated amounts of possible cationic active species and the uni‐ and bimodal catalytic behavior. Based on the results obtained, we concluded that the bimodal polyethylenes are produced by two kinds of cationic active species having two available cis‐located sites with cis‐N, trans‐O and cis‐N, cis‐O arrangements. The results introduced herein are rare examples of the production of well‐defined bimodal polyethylenes using a single precatalyst.

Bis(phenoxy imine) Zr complexes can produce well‐defined bimodal polyethylenes.