Multi-pulse drug delivery from a resorbable polymeric microchip device

Controlled-release drug delivery systems have many applications, including treatments for hormone deficiencies and chronic pain. A biodegradable device that could provide multi-dose drug delivery would be advantageous for long-term treatment of conditions requiring pulsatile drug release. In this work, biodegradable polymeric microchips were fabricated that released four pulses of radiolabelled dextran, human growth hormone or heparin in vitro. Heparin that was released over 142 days retained on average 96 +/- 12% of its bioactivity. The microchips were 1.2 cm in diameter, 480-560 microm thick and had 36 reservoirs that could each be filled with a different chemical. The devices were fabricated from poly(L-lactic acid) and had poly(D,L-lactic-co-glycolic acid) membranes of different molecular masses covering the reservoirs. A drug delivery system can be designed with the potential to release pulses of different drugs at intervals after implantation in a patient by using different molecular masses or materials for the membrane.     

New polymeric buffer materials with low driving voltage

We present excellent polymeric buffer materials based on the poly(9,9-dioctylfluorene-co-N, N-di(phenyl)-N,N-di(3-carboethoxyphenyl)benzidine) (BFE) for highly efficient solution processed organic light emitting diodes (OLEDs). Doped BFE with 3,5-dinitrobenzonitrile (35DNBN), a strong electron acceptor results in significant improvement of current flow and driving voltage. Maximum current- and power-efficiency value of 7.2 cd/A and 5.5 lm/W are demonstrated from blue OLEDs with these doped polymeric anode buffer system. The 40 nm thick anode buffer material showed a similar current density-voltage (J-V) behavior to that of PEDOT:PSS based device. Results reveal a practical way to fabricate the highly efficient solution processed devices for low cost production of printing devices for the future.     

Updates on smart polymeric carrier systems for protein delivery

Smart materials are those materials that are responsive to chemical (organic molecules, chemical agents or specific agents), biochemical (protein, enzymes, growth factors, substrates or ligands), physical (electric field, magnetic field, temperature, pH, ionic strength or radiation) or mechanical (pressure or mechanical stress) signals. These responsive materials interact with the stimuli by changing their properties or conformational structures in a predictable manner. Recently, smart polymers have been utilized in various biomedical applications. Particularly, they have been used as a platform to synthesize stimuli-responsive systems that could deliver therapeutics to a specific site for a specific period with minimal adverse effects. For instance, stimuli-responsive polymers-based systems have been recently reported to deliver different bioactive molecules such as carbohydrates (heparin), chemotherapeutic agents (doxorubicin), small organic molecules (anti-coagulants), nucleic acids (siRNA), and proteins (growth factors and hormones). Protein therapeutics played a fundamental role in treatment of various chronic and some autoimmune diseases. For instance insulin has been used in treatment of diabetes. However, being a protein in nature, insulin delivery is limited by its instability, short half-life, and easy denaturation when administered orally. To overcome these challenges, and as highlighted in this review article, much research efforts have been recently devoted to design and develop convenient smart controlled nanosystems for protein therapeutics delivery.     

Voltage distribution of two thin polymeric film surface resistancemeasurement systems

Two different methods for measuring the surface resistance of thin polymeric films are presented. The first method is the standard method and utilizes concentric ring metal electrodes. The second one is a novel method and uses instead concentric cylindrical metal electrodes. Both have been studied analytically and experimentally. The voltage distributions that are developed in both methods are calculated, plotted using three-dimensional graphs, and finally compared in order to analyze the advantages and disadvantages of the two measuring systems (acetate is the dielectric). The cylindrical electrodes, which give lower stresses around the outer electrode, seem to be more suitable for the measurements of the surface resistance of thin polymeric films     

Water sorption behaviour of polymeric systems based on tetrahydrofurfuryl methacrylate

Earlier research has described the water absorption behaviour, drug release and biological properties of a room temperature polymerizing system based on poly(ethyl methacrylate) (PEM) powder and tetrahydrofurfuryl methacrylate (THFM) monomer. This work has been extended, with respect to water sorption behaviour, by replacing the monomer to various extents with hydroxyethyl methacrylate (HEMA), and poly(ethyl methacrylate) by ethyl methacrylate (EM)-THFM copolymers. Replacing the THFM with HEMA, and gelling with PEM, increased the diffusion coefficient progressively. The replacement of PEM by EM-THFM copolymers, when gelled with THFM monomer, substantially reduced equilibrium water uptake, and increased diffusion coefficients. However, with HEMA monomer, equilibrium uptake was unaffected, but the diffusion coefficient decreased with increasing THFM content of the copolymer. This is due to a complex interaction of THFM cross-linking the copolymer, and the effect of EM on the water uptake. Heat polymerizing the PEM-THFM system reduced equilibrium uptake and the diffusion coefficient, compared with the room temperature polymerizing system; this could reflect molecular weight differences. © 1999 Kluwer Academic Publishers     

Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems

We describe the development of multifunctional polymeric micelles with cancer-targeting capability via alpha(v)beta(3) integrins, controlled drug delivery, and efficient magnetic resonance imaging (MRI) contrast characteristics. Doxorubicin and a cluster of superparamagnetic iron oxide (SPIO) nanoparticles were loaded successfully inside the micelle core. The presence of cRGD on the micelle surface resulted in the cancer-targeted delivery to alpha(v)beta(3)-expressing tumor cells. In vitro MRI and cytotoxicity studies demonstrated the ultrasensitive MRI imaging and alpha(v)beta(3)-specific cytotoxic response of these multifunctional polymeric micelles.     

海绵状电正性聚合物微粒的合成以及抗菌性

以甲基丙烯酸缩水甘油酯(GMA)和甲基丙烯酸甲酯(MMA)为单体、亚甲基双丙烯酰胺(BIS)为交联剂、琥珀酸二异辛酯磺酸钠(DOSS)为乳化剂,通过乳液聚合合成了带环氧结构的纳米聚合物粒子(EPPs)。EPPs与三甲胺盐酸盐反应后制得粒径增大数十倍的海绵状电正性聚合物微粒(CPPs),CPPs的电荷密度用胶体滴定法进行测定,其结构通过红外光谱进行了表征。用烧瓶振荡法研究了CPPs的抗菌性,结果表明,CPPs对大肠杆菌(E.coli)和金黄色葡萄球菌(S.aureus)的抑菌率均超过98.5%。     

Assessment of Bonelike® graft with a resorbable matrix using an animal model

Synthetic bone grafts have been developed to provide an alternative to autografts and allografts. Bonelike® is a patented synthetic osteoconductive bone graft that mimics the mineral composition of natural bone. In the present preliminary animal studies a user-friendly version of synthetic bone graft Bonelike® have been developed by using a resorbable matrix, Floseal®, as a vehicle and raloxifene hydrochloride as a therapeutic molecule, that is known to decrease osteoclast activity and therefore enhanced bone formation. From histological and scanning electron microscopy evaluations, the use of Bonelike® associated with Floseal® and raloxifene hydrochloride showed that new bone was rapidly apposed on implanted granules and also that the presence of the matrix and therapeutic molecule does not alter the proven highly osteoconductivity properties of Bonelike®. Therefore, this association may be one step-forward for the clinical applications of Bonelike® scaffolds since it is much more easy-to-handle when compared to granular materials.     

Evaluation of the dielectric parameters from TSDC spectra: application to polymeric systems

The Thermally Stimulated Discharge Current (TSDC) technique is widely used for the study of main and secondary dielectric relaxations in polymers. The TSD current is described by different equations that can be arranged in a unique three-parameters (the activation energy W, A and B) general form. The physical meaning of A and B depends on the origin of the discharge currents. In this paper a method is proposed to obtain these parameters by fitting the experimental data with the analytical expression of the current, in the range around the maximum. Simulations were carried out to underline the relative importance of the parameters. A method is proposed for the decomposition of experimentally determined complex bands into a limited number of elementary peaks, each of them characterized by average values for W and B. The errors resulting from different approximations used in the analytical current expression or by the utilization of various expressions for the relaxation time are analyzed. The method is applied for the analy-sis of the TSDC spectra in the glass-rubber transition temperature regions of PET and PMMA, yielding several peaks characterized by narrow distributions of W (ΔW≈± 0.06 eV). Received: 18 September 2000 / Reviewed and accepted: 20 September 2000     

聚合物基PTC热敏导电材料的性能及机理研究

针对PTC材料体系，提出了“PTC强度可提高空间”与“体系提高PTC强度的能力”两个概念，以低密度聚乙烯(LDPE)、高密度聚乙烯（HDPE)和乙烯-醋酸乙烯共聚物(EVA)作为基体，以导电炭黑作为填充导电粒子，制备了聚合物基复合型PTC材料，详细分析了炭黑含量、EVA含量对PTC材料性能的影响．研究表明，所提出的有关概念可用于分析材料的PTC效应机理及各种因素的影响，有助于进一步对聚合物基PTC热敏导电材料作用机制的理解及研究；炭黑含量影响材料电阻率和PTC强度，炭黑含量取在逾渗区电阻率偏小处可得到较高的PTC强度；EVA含量不同时材料电阻率和PTC强度都有先减小后稍增大的现象。     

New reliability modeling methods for structural systems with hybrid uncertainty

The present study investigates the hybrid reliability modeling of structures in which the inputs contain both random variables and interval variables. Hybrid uncertainty is divided into three categories, including random variables mixed with random variables, interval variables mixed with interval variable, and random variables mixed with interval variables. In order to perform the reliability analysis of structural systems, first, the Bayes method is proposed in the present study to obtain distribution parameters of random variables. Moreover, the self-sample method is introduced to obtain the interval boundaries based on the least available measuring data. Then, the reliability models are established for three situations and the reliability indices are defined and derived accordingly. The abovementioned three types of reliability indices outline the general situation of structural systems. Finally, the specific calculation process is described in details through different examples. Furthermore, the accuracy and efficiency of the proposed method is discussed by comparing the results obtained from the Monte Carlo simulation and those of other methods. The obtained results indicate that the performance of the proposed model in solving reliability modeling problems is better.     

Knowledge-based systems in the design activity

This paper considers the evolution of knowledge-based systems (KBS) in relation to the design activity. In order to do this effectively it commences with a definition of a core design activity in relation to products which are either conventional or novel. KBS are broken down in sympathy with the decomposition of a design, i.e., whole design, partial or sub-system design, component design. The problem of knowledge elicitation and the variability of the constraints at each level of design are considered and conclusions drawn in terms of conventional and novel products.

A hypothesis—‘to be or not to be’—is proposed covering the conceptual design spectrum which suggests that the way forward is via a system of linked KMs (knowledge modules) to be designed using multi-disciplinary teams, since it is considered that KBS are products in their own right and should be treated as such.     

Design of polymeric nanoparticles and its applications as drug delivery systems for acne treatment

Objective: The aim of this study was to evaluate a formulation made of poly(lactide-co-glycolide) (PLGA) nanoparticles containing azelaic acid for potential acne treatment.

Methods: Azelaic acid-loaded PLGA nanoparticles were prepared by spontaneous emulsification processes using poloxamer 188 as stabilizer. Several manufacturing parameters such as stirring rate, concentration of stabilizer and different recovery methods were investigated. Nanoparticles were evaluated in terms of size, zeta potential, encapsulation efficiency, release kinetics and permeation kinetics in vitro. Furthermore, in vitro toxicological studies were performed in Saccharomyces cerevisiae model.

Results: The results showed that by adjusting some formulation conditions it was possible to obtain nanoparticles with high loading and a controlled drug release. Freeze-dried recovery altered the nanoparticles structure by enhancing porous structures and mannitol was required to control the mean particle size. The centrifugation recovery was found to be the best approach to nanoparticles recovery. Similar toxicity profiles were observed for both drug-free and azelaic acid-loaded nanoparticles, with concentration-dependent decreases in cell viability.

Conclusion: These results indicate a potential formulation for controlled release delivery of azelaic acid to the follicular unit.     

The preparation of high conversion polymeric systems containing eugenol residues and their rheological characterization

Copolymeric systems bearing eugenol covalently linked to the macromolecular chains have been prepared and characterised in terms of thermal, rheological and in vitro behaviour. Eugenyl methacrylate (EgMA) and ethoxyeugenyl methacrylate (EEgMA) were polymerized and copolymerized with ethyl methacrylate (EMA) in a wide range of feed composition by bulk at high conversion. Glass transition temperature (T_g) increased with the content of EgMA in the copolymer whereas T_g decreased with the content of EEgMA. The presence of any of the eugenyl monomers in the copolymer increased the thermal stability of the materials. Rheological analysis showed that EMA-co-EgMA copolymers present a higher density of crosslinking or entanglements among the chains compared with EMA-co-EEgMA materials, and copolymers containing more than 40% EgMA exhibited a pseudo-solid like behaviour with G′ relatively independent of the frequency. The average molecular weight between cross-links (M_c) for the latter copolymers was in the order of 10⁴ Da. For EEgMA copolymers, tan δ was lower than unity and G′ showed a gradual and slight dependency with frequency over the whole range of composition. In vitro behaviour showed a higher hydrophilicity of the EEgMA containing copolymers manifested in higher water sorption values, lower water contact angle values and higher surface free energy due to an increase in polarity. All systems presented a good cytocompatibility with human fibroblasts assessed through direct and indirect assays.     

New paradigm for imaging systems

We describe a new paradigm for designing hybrid imaging systems. These imaging systems use optics with a special aspheric surface to code the image so that the point-spread function or the modulation transfer function has specified characteristics. Signal processing then decodes the detected image. The coding can be done so that the depth of focus can be extended. This allows the manufacturing tolerance to be reduced, focus-related aberrations to be controlled, and imaging systems to be constructed with only one optical element plus some signal processing.     

A hydrogen peroxide biosensor based on peroxidase activity of hemoglobin in polymeric film

A Hydrogen peroxide (H2O2) biosensor, based on hemoglobin (Hb) and ortho-phenylenediamine (o-PD) gold electrode, was fabricated. Hb was immobilized onto the electrode surface by electrochemical polymerize method with o-PD. The designed biosensor showed a well defined redox peak which was attributed to the direct electrochemical response of Hb. The immobilized Hb exhibited an excellent electrocatalytical response to the reduction of hydrogen peroxide, enabling the sensitivity determination of H2O2. Factors and performances such as pH, potential, influencing the designed biosensor, were studied carefully. The amperometric detection of H2O2 was carried out at -300 mV in phosphate buffer solution (PBS) (0.1 M) with pH 6.0. This biosensor showed a fast amperometric response (less then 5 s) to H2O2. The levels of the (Relative standard deviation) RSDs (< 3.5%) for the entire analyses reflected a highly reproducible sensor performance. Using the optimized conditions, the detection limit of the biosensor was 1 x 10(-7) M and linear range was from 5 x 10(-6) to 1.25 x 10(-4) M. In addition, this sensor showed long-term stability and good sensitivity.     

Improving anticancer activity and reducing systemic toxicity of doxorubicin by self-assembled polymeric micelles

In an attempt to improve anticancer activity and reduce systemic toxicity of doxorubicin (Dox), we encapsulated Dox in monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles by a novel self-assembly procedure without using surfactants, organic solvents or vigorous stirring. These Dox encapsulated MPEG-PCL (Dox/MPEG-PCL) micelles with drug loading of 4.2% were monodisperse and ～ 20 nm in diameter. The Dox can be released from the Dox/MPEG-PCL micelles; the Dox-release at pH 5.5 was faster than that at pH 7.0. Encapsulation of Dox in MPEG-PCL micelles enhanced the cellular uptake and cytotoxicity of Dox on the C-26 colon carcinoma cell in vitro, and slowed the extravasation of Dox in the transgenic zebrafish model. Compared to free Dox, Dox/MPEG-PCL micelles were more effective in inhibiting tumor growth in the subcutaneous C-26 colon carcinoma and Lewis lung carcinoma models, and prolonging survival of mice bearing these tumors. Dox/MPEG-PCL micelles also induced lower systemic toxicity than free Dox. In conclusion, incorporation of Dox in MPEG-PCL micelles enhanced the anticancer activity and decreased the systemic toxicity of Dox; these Dox/MPEG-PCL micelles are an interesting formulation of Dox and may have potential clinical applications in cancer therapy.