Synthesis,photocrosslinking characteristics,and biocompatibility evaluation of N‐vinyl pyrrolidone/polycaprolactone fumarate biomaterials using a new proton scavenger

Photocrosslinkable and biodegradable polymeric networks were formulated based on N‐vinyl pyrrolidone‐poly(ε‐caprolactone fumarate) (NVP/PCLF) compositions for hard tissue engineering applications using a new proton scavenger, propylene oxide (PO). The synthesized macromers were obtained as a white clear paste with no colorization. The obtained macromers were thoroughly characterized using spectroscopic (NMR and FT‐IR) and chromatographic (gel permeation chromatography (GPC)) techniques. Photocrosslinking of the PCLF/NVP compositions was achieved using camphorquinone and dimethyl toluidine (DMT) as a photoinitiator system. The cytocompatibility of the macromers and their corresponding networks were evaluated via MTT assay. Characterization of the networks indicated the importance of NVP content on the network properties. Sol fraction studies indicated that more than 90% of the PCLFs were crosslinked over the studied range of PCLF/NVP compositions; however most of the NVP above a stoichiometric ratio of one NVP to fumerate unit remained unreacted. It was also found that in the concentrations more than 10% NVP, the unreacted NVP monomer neither participated in the crosslinking reaction nor homopolymerized to poly(vinyl pyrrolidone) (PVP). The elastic modulus (G′) and estimated molecular weight between crosslinks also confirmed that at the higher NVP content the PCLF photocrosslinking was hindered. Copyright © 2008 John Wiley & Sons, Ltd.     

Comparative characterization of oligomeric precursors intended for injectable implants

The use of injectable materials is a simple approach for drug delivery and tissue repair, in, e.g. minimally invasive surgery applications. If these materials are used past their glass transition temperature and have a low viscosity, they will be able to flow while delivered in situ. Whether these materials are to be used as low viscosity drug carriers or further crosslinked for tissue repair, there is a need for a better understanding of their handling properties. In this study, oligo(trimethylene carbonate) (oTMC) and oligo[D,L‐lactide‐co‐(ε‐caprolactone)] (oDLLA‐co‐CL) of various molecular weights within a relevant injectability range were synthesized via ring‐opening polymerization. The materials were comparatively characterized by ¹H NMR spectroscopy, differential scanning calorimetry, gel permeation chromatography, and rheological measurements. After comparing the viscosities and molecular weights of the materials, it was concluded that oDLLA‐co‐CLs were, generally, better suited as an injectable in situ crosslinking network, whereas oTMCs were found to be better candidates as injectable drug carriers. This study provides useful data and guidelines on the use of these and other similar oligomers intended for injectable implants. Copyright © 2012 John Wiley & Sons, Ltd.     

Visible light-curable polymers for biomedical applications

Photocurable systems, which offer advantages such as microfabrication and in situ fabrication, have been widely used as dental restorative materials. Because the visible light-curable (VLC) system causes no biological damage, it is popular as a dental material and is being investigated by many researchers for other medical applications. Here, the principle of the VLC system is explained and recent progress in key components including photoinitiators, monomers, macromers, and prepolymers is discussed. Finally, biomedical applications for drug delivery and soft tissue engineering are reviewed. Considering the recent development of VLC systems, its importance in the field of medical applications is expected to continue to increase in the future.     

Infrared spectroscopy of electroluminescent conjugated polymers

The infrared spectra of the light-emitting diodes and the metal-insulator-semiconductor devices based on a poly(p-phenylenevinylene) derivative MEH-PPV have been measured in situ with a reflection configuration. The voltage-induced infrared spectra of these devices have been measured by the FT-IR difference-spectrum method. The observed bands have been attributed to the carriers injected into the polymer layers. The observation of positive carriers in the polymer light-emitting diode is probably related to the predominance of injected positive carriers, which is one of the factors in the low efficiency of the polymer light-emitting diode. In situ infrared reflective absorption measurements provide the information about injected carriers, which play a central role in the properties and the functions of polymer electronic devices.     

The effect of solvent composition on vancomycin hydrochloride and free base vancomycin release from in situ forming implants

In situ forming drug delivery systems that are formed by solvent‐induced phase inversion have attracted extensive attention in sustained delivery of peptides and proteins. Based on the findings of our previous studies, N‐methyl‐2‐pyrrolidone (NMP) and acetone are two solvents that could improve the release profile of vancomycin from in situ forming systems based on poly(D,L‐lactide‐co‐glycolic acid). In this study, the effect of different compositions of these solvents on the release profile of hydrochloride and free base forms of vancomycin was investigated. To this end, several formulations with vancomycin (either hydrochloride or free base form) and different proportions of NMP and acetone were prepared. The cumulative drug release at specified time was determined and tested against conventional kinetic models. The surface and cross‐sectional morphology of implants were investigated by SEM. The experimental results showed that as solvent composition changed, the amount of vancomycin release during the first 12 h changed, too. The use of free base vancomycin resulted in an extended vancomycin release profile with less initial burst release. The formulation containing free base vancomycin and mixed solvents of acetone and NMP in 2:1 ratio released 70% of loaded drug in 6 weeks with near zero‐order kinetic. The best kinetic model to fit the in vitro release profiles was found to be Peppas–Sahlin model. Copyright © 2016 John Wiley & Sons, Ltd.     

Tunable Amphiphilic Poly(Ether-Anhydride) Gel Nanoparticles for the Delivery of Hydrophobic Drugs

Summary: Biodegradable amphiphilic poly(ether-anhydride) gel nanoparticles (GNPs) with a hydrophobic crosslinked core and a hydrophilic PEG shell have been prepared from amphiphilic photo-crosslinkable ether-anhydride macromers via microemulsion photo-polymerization. The properties of the GNPs, such as degradability, size and drug-loading capacity, were investigated by tailoring the length of PEG chains in macromers from 400 to 4000 and by the addition of a hydrophobic photo-crosslinkable monomer: stearic monoacrylic anhydride (MSA). TEM showed that the GNPs were spherical in shape with a core-shell structure when MSA was added. The GNPs were used as the carriers to enhance the solubility of hydrophobic drugs. Indomethacin (IND) as a model drug was entrapped in the hydrophobic crosslinked core by an in situ embedding method. Results showed that IND maintained chemically intact during the formulation process, and its dissolution rate were improved compared to those of the pure IND. The GNPs prepared from PEG macromer (molecular weight: 4000) with the addition of MSA exhibited the zero-order release behavior, which is potentially useful to control the release of hydrophobic drugs.     

Synthesis and Characterization of Novel Amphiphilic Polymers as Drug Delivery Nano Carriers

Polymer nano-particles have been widely investigated in the last decade due to a variety of potential applications. In particular, polymers which can self assemble into micellar nano-particles can be effectively used as vehicles for drug delivery. Considerable efforts are underway to develop better drug delivery nano carriers for high drug loading capacity for a wide variety of bioactive compounds. In this study, several new polymers were synthesized in bulk (solventless condition) by a chemo-enzymatic methodology using Candida antarctica lipase B (Novozyme 435) and molecular sieves (MS). The synthesized polymers demonstrated high drug loading capacity and the potential to encapsulate drugs which are poorly soluble in aqueous solvents.     

Continuous Detection of pH‐responsive Drug Delivery System in Cells in situ by Confocal Laser Scanning Microscopy

Mesoporous silica nanoparticles (MSN) were coated by pH‐responsive polymer chitosan‐poly (methacrylic acid) (CS‐PMAA). This nano drug delivery system showed good application prospects and the polymer‐coated microspheres were promising site‐specific anticancer drug delivery carriers in biomedical field. A continuous detection of pH‐responsive drug delivery system in cells in situ, utilizing MSN/CS‐PMAA composite microspheres, was proposed. Two kinds of different cell lines, tumor cell line (Hela) and normal somatic cells (293T), were used to investigate the behaviours of the drug loaded system in the cells. Conclusions could be drawn from the fluorescent images obtained by confocal laser scanning microscopy (CLSM), modified drug‐loaded microspheres (MSN/CS‐PMAA) were ingested into cells more easily, the uptake of DOX@FITC‐MSN/CS‐PMAA by HeLa/293T cells were performed at pH 7.4/pH 6.8, DOX was released during the ingestion process, fluorescence intensity decreased with time because of efflux transport and photo‐bleaching. Fluoresence detection by flow cytometry was performed as comparison. The continuous fluorescent observation in situ could be widely used in the pH‐responsive releasing process of drug delivery system in the cells.     

Using hyperbranched macromers as crosslinkers of methacrylic networks prepared by photopolymerization

Hyperbranched polymers were modified with terminal methacryloyl groups to be used as crosslinkers. The photoinitiated polymerization of several methacrylic monomers was examined in the presence of the hyperbranched macromers and bis-(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure 819^®) as a photoinitiator, upon UV irradiation. The photopolymerization kinetics was systematically studied by fluorescence and photoDSC in real time and in situ. Six types of monofunctional methacrylic monomers, two types of difunctional methacrylic monomers and four types of (meth)acrylate-modified hyperbranched macromers with different structures were employed for series of photopolymerization reactions. The incorporation of the hyperbranched macromers allows to increase the conversion at gelation and thus, final conversion. This behaviour is dependent on monomer and macromer nature and has been explained as due to an increase of the free volume fraction and confirmed by fluorescence. The results indicate that H-bonding and π-stacking induce self-assembly of hyperbranched macromers leading to reaction induced phase separation at the highest concentration of hyperbranched macromer used.     

Polysaccharide gels for colon targeting

Polysaccharides appear to have a potential as drug carriers for site-specific drug delivery to the colon due to the well-known fermentation of polysaccharides by the anaerobic microflora in the colon. This paper gives a short presentation of the rationale of colon-specific drug delivery and briefly describes various in vitro and in vivo methods for testing of polysaccharide gels for colonic drug delivery. The application of dextran hydrogels is used as an illustrative example of a polysaccharide based colonic drug delivery system.     

Novel PEGylated Amphiphilic Copolymers as Nanocarriers for Drug Delivery: Synthesis,Characterization and Curcumin Encapsulation

Amphiphilic polymers can self assemble into micellar nano-particles and can be effectively used as nano carriers for drug delivery. A number of macromolecular delivery systems are under investigation to improve the efficacy of prospective drugs. In this study, seven new co-polymers were synthesized under mild reaction conditions in bulk (without solvent) by chemoenzymatic approach using Candida antarctica lipase (Novozyme 435) and molecular sieves, subsequently these polymers were treated with different long chain bromoalkanes and acid chlorides for attachment of the lipophilic moieties to the backbone polymer via an ether or an ester linkage, respectively in order to make them amphiphilic. These synthesized nano-particles demonstrated high drug loading capacity and have the potential to encapsulate hydrophobic drugs.     

Voltage-induced infrared spectra from polymer field-effect transistors

Charge-induced infrared absorption spectra from the metal-insulator-semiconductor diodes fabricated with aluminum oxide, poly(p-xylylene), and SiO₂ as gate dielectric and regioregular poly(3-octylthiophene) as organic semiconductor have been measured in situ with reflection or transmission configurations by the FT-IR difference-spectrum method. The observed bands have been attributed to the carriers injected into the polymer layers under the application of minus gate bias. The wavenumber of the band around 1300 cm⁻¹ depends on the gate voltage, indicating that the structure of the carriers depends on the carrier concentration. There exist upper limits in the concentrations of the injected carriers. In situ infrared absorption measurements provide the information about the injected carriers, which affect the properties and the functions of polymer field-effect devices.     

γ‐Butyrolactone Copolymerization with the Well‐Documented Polymer Drug Carrier Poly(ethylene oxide)‐block‐poly(ε‐caprolactone) to Fine‐Tune Its Biorelevant Properties

Polymeric drug carriers exhibit excellent properties that advance drug delivery systems. In particular, carriers based on poly(ethylene oxide)‐block‐poly(ε‐caprolactone) are very useful in pharmacokinetics. In addition to their proven biocompatibility, there are several requirements for the efficacy of the polymeric drug carriers after internalization, e.g., nanoparticle behavior, cellular uptake, the rate of degradation, and cellular localization. The introduction of γ‐butyrolactone units into the hydrophobic block enables the tuning of the abovementioned properties over a wide range. In this study, a relatively high content of γ‐butyrolactone units with a reasonable yield of ≈60% is achieved by anionic ring‐opening copolymerization using 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene as a very efficient catalyst in the nonpolar environment of toluene with an incorporated γ‐butyrolactone content of ≈30%. The content of γ‐butyrolactone units can be easily modulated according to the feed ratio of the monomers. This method enables control over the rate of degradation so that when the content of γ‐butyrolactone increases, the rate of degradation increases. These findings broaden the application possibilities of polyester‐polyether‐based nanoparticles for biomedical applications, such as drug delivery systems.     

Preparation and characterization of novel silk fibroin/2-(N,N-dimethylamino)ethyl methacrylate based composite hydrogels with enhanced mechanical properties for controlled release of cefixime

Hydrogels with improved mechanical properties have been particularly attractive for their applications in the biomedical area including wound healing. For this purpose, a series of novel composite hydrogels based on silk fibroin (SF) and 2-(N,N-dimethylamino) ethyl methacrylate (DMAEMA) were fabricated. The swelling and mechanical tests indicated that an optimum design of hydrogel was essential to provide a high degree of water uptake, higher tensile strength and elongation at break values. Here, the S40D60 was exhibited superior swelling and strong mechanical characteristics than all the other hydrogels with different compositions. Furthermore, it was observed that the cefixime was released from the formulation of S40D60 in a sustainable manner and the drug release rate can be controlled by pH of the dissolution medium. According to these findings, it is suggested that the optimal formulation of S40D60 would be effectively performed in situ drug therapy for wound healing.     

Silk‐Ion Jelly: a novel ion conducting polymeric material with high conductivity and excellent mechanical stability

In this work, a thin, flexible and mechanically stable polymer conducting material (Silk‐Ion Jelly) was developed though application of Ion Jelly on to silk fabrics. Ion Jelly was prepared through jellification of a room temperature ionic liquid, 1‐butyl‐3‐methyl‐imidazolium dicyanamide ([bmim][dca]) using gelatin and water and applied to silk fabrics using two different processes: impregnation and in‐situ. Various parameters influencing ionic conductivity such as Ion Jelly composition (ratio of [bmim][dca], water and gelatin) and incorporation as well as the type of application process were thoroughly investigated. It was observed that the Ion Jelly compositions containing lower gelatin and water ratio as well as application through in‐situ process at high temperature (200 °C) led to considerable improvement in conductivity, mainly due to increased [bmim][dca] concentration, structural flexibility and reduced silk crystallinity. Silk‐Ion Jelly prepared using optimized conditions showed excellent mechanical stability and possessed high room temperature conductivity (2.9 × 10^?3 S. cm^?1), similar to [bmim][dca], and therefore, this novel ion conducting material may find potential applications in electrochemical devices due to its eco‐friendly preparation route using biomaterials and green solvents. Copyright © 2012 John Wiley & Sons, Ltd.     

Radiation synthesis of poly[(dimethylaminoethyl methacrylate)-co-(ethyleneglycol dimethacrylate)] hydrogels and its application as a carrier for anticancer delivery

The use of hydrogels as carriers for anticancer delivery has been a subject of significant recent research. In our recent work, we have shown that diffusion-controlled delivery of flutamide from hydrogels containing poly (dimethylaminoethyl methacrylate (DMAEMA)/ethyleneglycol dimethacrylate (EGDMA)) can be possible and controlled by the three-dimensional structure. Hydrogels based essentially on dimethylaminoethyl methacrylate and different ratios of ethyleneglycol dimethacrylate monomers were synthesized using gamma radiation copolymerization. The influence of copolymer composition and pH value of the surrounding medium on swelling behavior into the glassy polymer were discussed. The results showed that the ratio of EGDMA in the comonomer feeding solution has a great effect on the gel fraction and water content in the final hydrogel. In this regard, it was observed that the increase of EGDMA ratio decreased these properties. The ability of the prepared copolymer to be used as drug carrier for anticancer drug-delivery system was estimated using flutamide as a model drug. In vitro drug-release studies in different buffer solutions show that the basic parameters affecting the drug release behavior of hydrogel are the pH of the solution and DMAEMA content of hydrogel.     

Biodegradable polycaprolactone–polyanhydrides blends

Biodegradable polymers based on a blend of polycaprolactone (PCL) and aliphatic polyanhydrides with various monomer lengths were prepared to obtain desired polymer blends for use as drug carriers. The physicochemical, mechanical, and drug‐release properties of these blends were investigated by various techniques to evaluate the uniformity degree of the polymer blends to establish their potential applications in drug delivery. The results demonstrated that the heat of fusion (ΔH) of the polyanhydride or the blend is increased in relation to the length of the aliphatic chain. However, the blends had different properties than pure polyanhydride, and the crystallization degree of the blends, as expressed by the ΔH, decreased in relation to the ΔH of the pure polyanhydride. Drug‐release studies from blends of PCL and aliphatic polyanhydrides demonstrated first‐order kinetics of the release rate. Polymer degradation was independent at the polyanhydride monomer length. On the basis of theoretical calculation of the interaction factor, a blend of PCL and poly(dodecanedeoic anhydride) was chosen for further elucidation of its thermal, mechanical, and degradation properties. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3781–3787, 2003     

Development of low-cost planar electrodes and microfluidic channels for applications in capacitively coupled contactless conductivity detection (C4D)

Electrochemical techniques are commonly applied to micro total analysis system (μTAS) devices mainly due to its high sensitivity and miniaturization capacity. Among many electrochemical techniques, capacitively coupled contactless conductivity detection (C⁴D) stands out for not requiring direct electrode-solution contact, avoiding several problems such as electrolysis, bubble formation, and metal degradation. Furthermore, the instrumentation required for C⁴D measurements is compact, low cost, and easy to use, allowing in situ measurements to be performed even by nonspecialized personal. Contrarily, the production of metallic electrodes and microchannels adequate for C⁴D measurements commonly requires specialized facilities and workers, increasing the costs of applying these methods. We propose alternatives to batch manufacture metallic electrodes and polymeric microchannels for C⁴D analysis using more straightforward equipment and lower-cost materials. Three devices with different dielectric layer compositions and electrode sizes were tested and compared regarding their analytical performance. The constructed platforms have shown a reduction of more than 64% in cost when compared to traditional techniques and displayed good linearity (R² ≥ 0.994), reproducibility (RSD ≤ 4.07%, n = 3), and limits of detection (≤0.26 mmol/L) when measuring standard NaCl samples. Therefore, the proposed methods were successfully validated and are available for further C⁴D applications such as diagnosis of dry-eye syndrome.     

Synthesis and characterization of hydrophilic polyester‐PEO networks with shape‐memory properties

Shape‐memory polyester‐polyethylene oxide networks are synthesized through photopolymerization of hydrophobic poly[(D,L‐lactide)‐co‐glycolide]tetraacrylate (PLGATA) and hydrophilic poly(ethylene glycol) dimethacrylate (PEGDMA). The materials can recover their original shape either quickly by heating stimulus or slowly upon immersion in water. The wettability, mechanical properties, and transition temperature of the polymer networks could be conveniently adjusted by variation of the compositions of PLGATA and PEGDMA. The hydrophilicity of PEGDMA could prospectively improve blood compatibility of polymer networks. They offer a high potential for biomedical applications such as smart implants, drug delivery systems, or medical devices. Copyright © 2010 John Wiley & Sons, Ltd.     

Supramolecular Drug Delivery Systems Based on Water‐Soluble Pillar[n]arenes

Supramolecular drug delivery systems (SDDSs), including various kinds of nanostructures that are assembled by reversible noncovalent interactions, have attracted considerable attention as ideal drug carriers owing to their fascinating ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, which provides a flexible and robust platform for designing and developing functional and smart supramolecular nano‐drug carriers. Pillar[n]arenes represent a new generation of macrocyclic hosts, which have unique structures and excellent properties in host–guest chemistry. This account describes recent progress in our group to develop pillararene‐based stimuli‐responsive supramolecular nanostructures constructed by reversible host–guest interactions for controllable anticancer drug delivery. The potential applications of these supramolecular drug carriers in cancer treatment and the fundamental questions facing SDDSs are also discussed.