Overcoming the Inflammatory Toxicity of Cationic Gene Vectors

Cationic lipid- and polymer-based vectors are the most extensively studied synthetic gene vectors. These vectors have been widely used in animal models and some have been tested in clinical trials. The clinical progress of these vectors has been slowed by their inflammatory toxicity. This review summarizes the observations, the mechanisms, and various strategies employed to overcome the inflammatory toxicity of cationic gene vectors.     

Targeting HbS Polymerization

The mutation of β6 from glu to val in hemoglobin is responsible for the polymer formation that leads to vaso-occlusion, and a range of severe consequences in sickle cell disease. The treatment of the disease can be addressed in many ways, but the prevention of polymer formation is one of the most fundamental approaches one can take. Such prevention includes affecting the polymer structure, or dilution of the fraction of polymerizable hemoglobin. The latter approach includes (1) induction of HbF, which does not itself, nor in hybrid form, join sickle polymers, or (2) restricting the allosteric change in hemoglobin that occurs in oxygen delivery, and which is required for polymer formation. These approaches will be critically reviewed, as well as the most recent developments that show the benefits of simply swelling the volume of the red cell.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Photopolymerization shrinkage-stress reduction in polymer-based dental restoratives by surface modification of fillers

ObjectivesThis research explores the use of polymer brushes for surface treatment of fillers used in polymer-based dental restoratives with focus on shrinkage stress reduction. The influence of interfacial reactive groups on shrinkage stress is explored.MethodsOligomers of varying lengths and with varying number of reactive groups along the length were synthesized by modifying commercial oligomers. Surface of silica fillers (OX50) was treated with methylaminopropyltrimethoxysilane and this was further reacted with the synthesized oligomers to obtain a series of polymer brushes on the surface. Fillers modified with γ-methacryloxypropyltrimethoxysilane were used as a control. Filler surface treatment was confirmed using diffuse reflectance spectroscopy and thermogravimetric analysis. Fillers were added at 30 wt % to a resin made of BisGMA/TEGDMA and polymerization kinetics, shrinkage stress, volumetric shrinkage, flexural strength and modulus, viscosity were measured.ResultsComposites with polymer brush functionalized fillers showed up to a 30 % reduction in shrinkage stress as compared to the control, with no reduction in flexural strength and modulus. Shrinkage stress reduced with increasing length of the polymer brush and increased with increase in number of reactive groups along the length of the polymer brush.SignificanceThe interface between inorganic fillers and an organic polymer matrix has been utilized to reduce shrinkage stress in a composite with no compromise in mechanical properties. This study gives insights into the stress development mechanism at the interface.     

Adhesion to high-performance polymers applied in dentistry: A systematic review

ObjectiveThe aim of this systemic review, conducted in accordance with the PRISMA statement, was to investigate the impact of surface pretreatments on the bonding strength of high performance polymers (HPPs).MethodsEight databases were searched through March 2019. Risk of bias was assessed and random effects meta-analyses were applied to analyze mean differences in shear bond strength (SBS) and tensile bond strength (TBS), considering surface pretreatments and bonding agents after 24h and thermocycling.ResultsA total of 235 relevant titles and abstracts were found, yielding 11 final selections. Low risk of bias was observed in most studies. For polyetheretherketone (PEEK) specimens, random-effect models showed that, compared to non-treated controls, pretreatments associated with Visio.link® (Bredent, Senden, GE) increased TBS by 26.72 MPa (95% confidence interval (CI), 19.69–33.76; p < 0.00001) and increased SBS by 4.86 MPa (95% CI, 2.61–7.10; p < 0.00001). Air abrasion improved SBS by 4.90 MPa (95% CI, 3.90–5.90; p < 0.00001) (50 μm alumina) and 4.51 MPa (95% CI, 1.85–7.18; p = 0.0009) (silica-coated CoJet). In comparison to non-treated controls, Visio.link® and Signum PEEK Bond® (Heraeus Kulzer, Hanau, GE) increased SBS by 33.76 MPa (95% CI, 18.72–48.81; p < 0.00001) and 33.28 MPa (95% CI, 17.48–49.07; p < 0.00001), respectively. No differences were found between Visio.link® and Signum PEEK Bond® or Monobond Plus/Heliobond® (Ivoclar Vivadent, Schaan, LH) (p > 0.05). Similar results were observed for polyetherketoneketone (PEKK) specimens.SignificanceThis review shows improved HPP bonding following the application of various surface pretreatments, including air abrasion and bonding agents.     

头孢地尼原料及制剂的聚合物杂质分析

目的 建立头孢地尼原料及制剂聚合物杂质的分析方法。方法 分别采用0.1mol/L磷酸盐溶液和氯仿-三乙胺为溶剂,制备头孢地尼降解溶液;采用高效凝胶色谱法(HPSEC, TSK G2000 SWxl)和柱切换-LC/MSn法对头孢地尼降解溶液的弱保留值杂质进行分离和结构鉴定,并评估高效凝胶色谱法分析聚合物杂质的专属性;采用Diamonsil, C18型色谱柱,以0.25%四甲基氢氧化铵溶液(pH5.5)-甲醇-乙腈为流动相进行梯度洗脱,建立头孢地尼聚合物的RP-HPLC分析方法,采用二维色谱法和柱切换-LC/MSn法对其专属性进行分析,并进行方法学验证。结果 在头孢地尼降解物中鉴定出头孢地尼二聚体及其异构体,以及若干小分子杂质;高效凝胶色谱法分离头孢地尼聚合物杂质时,小分子杂质与聚合物杂质共出峰,方法专属性与定量准确性差;RP-HPLC法分析头孢地尼聚合物杂质时,能够检出头孢地尼二聚体及其异构体,头孢地尼三聚体,专属性好。结论 高效凝胶色谱法不能对头孢地尼的聚合物杂质进行有效质控,建立的反相色谱法分析头孢地尼聚合物杂质的专属性良好,可将头孢地尼降解溶液可作为聚合物杂质系统适用性溶液。     

Microtopography and Soft Tissue Response

Implants placed in soft tissue evoke a foreign body reaction. Polymeric implants having smooth surfaces, such as silicone rubber implants, develop a nonadherent fibrogranulous tissue capsule which contracts over time and stiffens. Conventional porous implants, such as those made from textiles, usually have pores larger than 20 μm and they become infiltrated with inflammatory tissue. The in vivo cell reaction to polymeric surfaces having pores smaller than 10 μm has not been investigated systematically. In this study the histocompatibility of materials having mean pore diameters from 0.4 to 10 μm was assessed. A material available with several different defined pore sizes Versapor filter material) was tested in vivo to determine relation between pore size and qualitative tissue response. Silicone-coated samples were also tested to determine the dependence of the observed tissue response on the implant surface chemistry. Results showed nonadherent, contracting capsules around implants having pore diameters smaller than 0.5 μm. Implants with pores ranging from 1.4 to 1.9 μm evoked thin, tightly adherent fibrous capsules without inflammatory cells. Porosities of 3.3 μm and larger became infiltrated with inflammatory tissue. Results indicate that the obsexrved tissue response is predominantly dependent on implant surface topography and that variation in implant material may have little effect. It is concluded that a defined surface topography of 1 to 2 pm appears to allow direct fibroblast attachment to the surface independent of its chemical or electrochemical nature. Attached fibro-blasts then produce a minimal connective tissue response to the implant and prevent or diminish the presence of inflammatory cells at the implant/tissue interface.     

Dimethacrylate network formation and polymer property evolution as determined by the selection of monomers and curing conditions

Objectives

This overview is intended to highlight connections between monomer structure and the development of highly crosslinked photopolymer networks including the conversion dependent properties of shrinkage, modulus and stress.

Methods

A review is provided that combines the polymer science and dental materials literature along with examples of relevant experimental results, which include measurements of reaction kinetics, photorheology as well as polymerization shrinkage and stress.

Results

While new monomers are continually under development for dental materials applications, mixtures of dimethacrylate monomers persist as the most common form of dental resins used on composite restorative materials. Monomer viscosity and reaction potential is derived from molecular structure and by employing real-time near-infrared spectroscopic techniques, the development of macromolecular networks is linked to the evolution of polymerization shrinkage (measured by linometer), modulus (measured by photorheometer), and stress (measured by tensometer). Relationships between the respective polymer properties are examined.

Significance

Through a better understanding of the polymer network formation and property development processes using conventional dimethacrylate monomer formulations, the rational design of improved materials is facilitated with the ultimate goal of achieving dental polymers that deliver enhanced clinical outcomes.     

Carbon nanotube-based self-adhesive polymer electrodes for wireless long-term recording of electrocardiogram signals

In this study, the concept of polymer electrodes integrated with a wireless electrocardiogram (ECG) system was described. Polymer electrodes for long-term ECG measurements were fabricated by loading high content of carbon nanotubes (CNTs) in polydimethylsiloxane. Silver nanoparticles (Ag NPs) were added to increase the flexibility of the polymer and the conductivity of the electrode. An ECG electrode patch was fabricated by integrating the electrodes with an adhesive polydimethylsiloxane (aPDMS) layer. Holes in the electrode filled with aPDMS can enable robust contact between the electrode and skin, reducing motion artifacts. A wireless ECG measurement system was developed and adapted to the polymer electrodes. The polymer electrodes combined with the measurement system were successfully applied in wireless, long-term recording of ECG signals. An eleven-day continuous test showed that the ECG signal did not degrade over time. The results of attach/detach tests demonstrated that the ECG signal was affected by motion artifacts after six attach/detach cycles. The electrodes produced are flexible and exhibit good ECG performance, and therefore can be used in wearable medical monitoring systems. The approach proposed in this study holds significant promise for commercial application in medical fields.     

Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-β peptide (Aβ) and especially the Aβ peptide 1-42 (Aβ_1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aβ_1-42 in the blood and promote its elimination through the “sink effect” and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aβ_1-42. Treatment of AD-like transgenic mice with anti-Aβ_1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aβ soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aβ levels in plasma. This study represents the first example of Aβ_1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.