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Polymer particle-based micromolding to fabricate novel microstructures.

Conventional micromolding provides rapid and low-cost methods to fabricate polymer microstructures, but has limitations when producing sophisticated designs. To provide more versatile micromolding techniques, we developed methods based on filling micromolds with polymer microparticles, as opposed to polymer melts, to produce microstructures composed of multiple materials, having complex geometries, and made using mild processing conditions. Polymer microparticles of 1 to 30 microm in size were made from PLA, PGA and PLGA using established spray drying and emulsion techniques either with or without encapsulating model drug compounds. These polymer microparticles were filled into PDMS micromolds at room temperature and melted or bonded together to form microstructures according to different protocols. Porous microstructures were fabricated by ultrasonically welding microparticles together in the mold while maintaining the voids inherent in their packing structure. Multi-layered microstructures were fabricated to have different compositions of polymers and encapsulated compounds located in different regions of the microstructures. More complex arrowhead microstructures were fabricated in a two-step process using a single mold. To assess possible applications, microstructures were designed as microneedles for minimally invasive drug delivery. Multi-layer microneedles were shown to insert into cadaver tissue and, according to design, detach from their base substrate and remain embedded in the tissue for controlled release drug delivery over time. We conclude that polymer particle-based micromolding can encapsulate compounds within microstructures composed of multiple materials, having complex geometries, and made using mild processing conditions.

Biocompatible Materials↗

Effect of polymer blending on the release of ganciclovir from PLGA microspheres.

PURPOSE: The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. METHODS: Two grades of PLGA, PLGA 7525 [D,L-lactide:glycolide(75:25), MW 90,000-126,000 Da] and Resomer RG 502H [D,L-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. RESULTS: Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R2 values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70-95%) was released during the matrix degradation cum diffusion phase. CONCLUSIONS: Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502HColon, two colons 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.

Algorithms↗

Complexes between synthetic polymer ligands and ferri-delta and ferro-protoporphyrin IX.

The complexes of synthetic polymer ligands, i.e. poly-L-lysine, poly-4-vinyl-pyridine, poly-N-vinyl-2-methylimidazole and the higher branched polyethyleneimine, with ferri- or ferro-protoporphyrin IX were studied from the standpoint of polymer ligand effects by comparison with those of their monomeric model ligand complexes and poly-gamma-benzyl-L-glutamate containing an imidazole nucleus at the chain end. The coordination numbers and formation constants were determined optically and their structures were also estimated. The coordination number of a poly-L-lysine complex was two, but those of other polymer ligand complexes were one. One of the polymer effects, which was indicated by the large formation constants of the polymer complexes, was caused by the increment of the local ligand concentration around the polymer chain. Another was caused by the conformational effect of an alpha-helical structure in the poly-L-lysine complexes. The interaction of a poly-L-lysine-heme complex with molecular oxygen was also studied. An observed pseudo-allosteric phenomenon may be due to the specific structure of a poly-L-lysine complex which is different from those of other polymer ligand complexes.

Allosteric Site↗

Cell adhesion and growth on polymer surfaces with hydroxyl groups prepared by water vapour plasma treatment.

Various polymer surfaces--polyethylene, polypropylene, polystyrene, polyethylene terephthalate and poly(methyl methacrylate)--were modified by water vapour plasma discharge treatment. The plasma-treated polymer surfaces were characterized by water contact angle measurement and electron spectroscopy for chemical analysis. It was observed that by the water vapour plasma treatment, the wettability of the polymer surfaces increases largely and almost all functional groups produced on the surfaces are hydroxyl groups. The interactions of Chinese hamster ovary cells with the polymer surfaces having hydroxyl groups by plasma treatment were investigated. The cells adhered and grown on the polymer surfaces were counted using a haemocytometer and photographed with an inverted microscope with a camera attached. The water vapour plasma-treated polymers showed good adhesion, spreading and growth properties on the surfaces with high hydroxyl group density. We confirmed that the water vapour plasma treatment is a simple and effective method to produce hydroxyl groups on the polymer surfaces, which probably have a positive effect on cell adherence.

Animals↗

Surface coating of hydrophilic-hydrophobic block co-polymers on a poly(acrylonitrile) haemodialyser reduces platelet adhesion and its transmembrane stimulation.

Surface design aimed at reduced adhesion and preserved functions of platelets is of great importance for extracorporeal devices. In this study, a coating technique using hydrophilic-hydrophobic block co-polymers on a hydrophobic poly(acrylonitrile) (PAN) haemodialyser was explored. The hydrophilic block of co-polymers was composed of either poly(methoxy polyethylene glycol methacrylate) or poly(dimethyl acrylamide), and the hydrophobic block was poly(methyl methacrylate). The co-polymers were coated on the dialyser membrane by means of a solution coating method. Upon coating, the hydrophobic block of the co-polymers was anchored on a PAN membrane and the hydrophilic block oriented towards the blood-material interface. This was deduced from water wettability measurements. Significantly reduced transmembrane stimulation of platelets was observed, which was evaluated by determining the intracellular calcium ion concentration of platelets eluted through treated hollow fibres. This suppression was enhanced as the relative fraction of the hydrophilic block of the co-polymers increased. Furthermore, the number of platelets adhering to the co-polymer-coated PAN membrane was drastically reduced. Thus, coating of the hydrophilic-hydrophobic block co-polymers provided better biocompatibility on a hydrophobic PAN dialyser.

Acrylamides↗

Evaluation of wear in an all-polymer total knee replacement. Part 2: clinical evaluation of wear in a polyethylene on polyacetal total knee.

In an effort to improve the long-term result of total joint replacement arthroplasty, we have investigated the use of a polymer-on-polymer articular replacement arthroplasty. Because of their known biocompatibility and previous use in orthopedic surgery, polyethylene and polyacetal (copolymer, Hoechst) were selected. Polyethylene served in its usual role as the concave member of the articulation; polyacetal formed the convex number. Formal wear testing using a multi-channel hip simulator demonstrated superior wear characteristics of the polymer-on-polymer configuration compared to a conventional chrome-cobalt versus polymer (polyethylene) configuration. A clinical series of relatively high-activity patients having a minimum five-year follow-up (N = 26) showed no specific unfavorable reaction to this material combination in a total knee replacement. Given certain potential advantages of polymeric materials, as well as some theoretical disadvantages of metallic materials, a polymer-on-polymer design for a large joint replacement may have some merit.

Acetals↗

Pulse injection analysis of the binding of serum proteins to porous polymer gels modified with formyl groups.

Highly porous spherical polymer gels were modified with formyl groups by a modified Friedel-Crafts reaction and the interaction of serum proteins with the modified gels were examined by pulse injection analysis. The introduction of formyl groups into the polymer greatly increases its protein-binding capacity, and the protein bound to the gel is not eluted by washing with acid, alkali or urea solution. The effects of temperature and the percentage of formyl group substitution on the binding capacity indicate that the binding process can be interpreted as initial approach of the protein to the polymer surface, caused by the hydrophobic interaction, followed by formation of a stable Schiff base between the polymer gel and the protein. Theoretical treatment of the elution behaviour of the protein from the polymer-packed column is also examined, with the assumption that there are three kinds of binding site in the polymer gel: surface, macropore and micropore regions. These polymers are shown to be useful for the removal of proteins from biological samples in clinical assays using immobilized enzymes.

Animals↗

Effects of increasing polymer hydrophobicity on distribution ratios of TcO4- in polyethylene/poly(propylene glycol)-based aqueous biphasic systems.

The partitioning behavior of the pertechnetate anion was studied in aqueous biphasic systems (ABS) formed from (NH4)2SO4 and four types of polymers-poly)ethylene glycol) PEG, poly(propylene glycol) (PPG), Pluronic (a PEG/PPG block copolymer), and polyvinylpyrrolidone (PVP). Phase diagrams are reported for five (NH4)2SO4-polymer ABS systems including the polymers PEG-2000, PEG-3400, PEG-12,000, Pluronic-L64 (average molecular mass approximately 2900), and PVP-K15 (average M(r) approximately 10,000). Distribution ratios for the TcO4- anion in each of these ABS were investigated as a function of increasing salt concentration. In addition, the water-insoluble polymer PPG-2000 was studied. Pertechnetate partitions nearly quantitatively to the polymer-rich phase in each ABS, however, distribution ratios of near one were found for the PPG system. The relative ordering of the distribution ratios is PPG << PVP << PEG-2000 < PEG-3400 approximately PEG-12,000 < Pluronic-L64 for the three PEG-ABS systems, distribution ratios of the sulfate anion decrease in the order PEG-2000 > PEG-3400 > PEG-12,000, exhibiting the expected increase in phase incompatibility with increasing polymer M(r). Investigation of pertechnetate partitioning in two additional ABS based on K3PO4 and NaOH with Pluronic-L64 revealed trends similar to those reported for PEG-2000; the distribution ratio (D) values increase in the order NaOH < (NH4)2SO4 < K3PO4. Despite the higher distribution ratios from Pluronic-L64 at lower concentrations than found for PEG, the limited useable range of salt concentrations available may limit the practical utilization of this polymer in ABS separations.

Nephelometry and Turbidimetry↗

Synthetic strategies for the generation of molecularly imprinted organic polymers.

Molecular imprinting is a method of inducing molecular recognition properties in synthetic polymers in response to the presence of a template species during formation of the three-dimensional structure of the polymer. The molecularly imprinted polymers (MIPs) prepared in this way have been termed "plastic antibodies" and combine the robustness of the polymer scaffold with binding properties more readily associated with biological receptors. Smart polymers of this type may find applications in drug delivery, controlled release and monitoring of drug and metabolite concentrations. In this review the main synthetic strategies used in the preparation of imprinted organic polymers are described in terms of the chemical principles used in the templating step. These are illustrated with examples taken from the literature and are classified as covalent, semi-covalent, non-covalent, metal-mediated and non-polar. Finally strategies for the selection of monomers, optimisation and modification of the properties of imprinted polymers are reviewed.

Binding Sites↗

Adhesion and proliferation of cells on new polymers modified biomaterials.

Up to today, several techniques have been used to maintain cells in culture for studying many aspects of cell biology and physiology. More often, cell culture is dependent on proper anchorage of cells to the growth surface. Poly-l-lysine is commonly used as adhesive molecule. In this study, we present, as an alternative to poly-l-lysine, new polymer film substrates, realized by electropolymerization of different monomers on fluorine-doped tin oxide (FTO) surfaces since electropolymerization is a good method to coat selectively metallic or semiconducting electrodes with polymer films. So, the adhesion, proliferation and morphology of rat neuronal cell lines were investigated on polymer treated surfaces. Several amine-based biocompatible polymers were tested: polyethyleneimine (PEI), polypropyleneimine (PPI), polypyrrole (PPy) and poly(p-phenylenediamine) (PPPD). These polymer films were coated on FTO surfaces by electrochemical oxidation. After 8 h in a culture medium, a high percentage of cells was found to be attached to PEI and PPI compared to the other polymers and to the reference surfaces (glass and FTO uncovered). After 24 and 72 h in the culture medium, cells were found to proliferate faster on PEI and PPI than on other polymers and reference surfaces. Consequently, cells have a greater fold expansion on PEI and PPI than on PPPD, PPy or glass and FTO uncoated. From these results, we deduce that PEI and PPI can be useful as coating surface to cultivate neuronal cells.

Amines↗

Monitoring cell adhesion processes on bioactive polymers with the quartz crystal resonator technique.

The Thickness Shear Mode (TSM) quartz crystal resonator has been extensively used as sensitive sensor in various electrochemical and biological applications. This technique based on the propagation of an ultrasonic shear wave generated by a sinusoidal electric field through a piezoelectric quartz resonator, provides a non-destructive and powerful means to probe changes at solid-solid or solid-liquid interfaces. In this study, TSM was used to characterize cell-polymer interactions developing during the cell adhesion process. TSM sensing was used to monitor the inhibiting properties of bioactive polymers towards fibroblast McCoy adhesion processes. For this purpose, thin films of various bioactive polymers exhibiting either carboxylate or/and sulfonate functional groups were deposited onto the TSM. Measurements of the time variation of the electrical motional resistance in the vicinity of the mechanical sensor resonant frequency were performed as the quartz crystal resonator was either coated with the continuous polymer phase or polymer plus cell suspensions. Cell adhesion processes on these surfaces was investigated by cell counting and the quartz resonator-based technique. Inhibition of fibroblast McCoy adhesion onto thin polymer films of various chemical compositions was analyzed and discussed in the perspective of a possible application of these bioactive polymers to fabricate intraocular lenses able to prevent secondary cataract phenomena.

Biocompatible Materials↗

Towards a methodology for the effective surface modification of porous polymer scaffolds.

A novel low-pressure radio-frequency plasma treatment protocol was developed to achieve the effective through-thickness surface modification of large porous poly (D,L-lactide) (PDLLA) polymer scaffolds using air or water: ammonia plasma treatments. Polymer films were modified as controls. Scanning electron micrographs and maximum bubble point measurements demonstrated that the PDLLA foams have the high porosity, void fraction and interconnected pores required for use as tissue engineering scaffolds. The polymer surface of the virgin polymer does contain acidic functional groups but is hydrophobic. Following exposure to air or water: ammonia plasma, an increased number of polar functional groups and improved wetting behaviour, i.e. hydrophilicity, of wet surfaces was detected. The number of polar surface functional groups increased (hence the decrease in water contact angles) with increasing exposure time to plasma. The change in surface composition and wettablility of wet polymer constructs was characterised by zeta potential and contact angle measurements. The hydrophobic recovery of the treated PDLLA polymer surfaces was also studied. Storage of the treated polymer constructs in ambient air caused an appreciable hydrophobic recovery, whereas in water only partial hydrophobic recovery occurred. However, in both cases the initial surface characteristics decay as function of time.

Absorbable Implants↗

Blood compatibility of novel water soluble hyperbranched polyglycerol-based multivalent cationic polymers and their interaction with DNA.

A novel class of hyperbranched polymers based on polyglycerol (PG) and poly(ethylene glycol) (PEG) are synthesized by multibranching anionic ring opening polymerization. Multivalent cationic sites are added to these polymers by a post-amination and quarternization reactions. Blood compatibility studies using these polymers at different concentrations showed insignificant effects on complement activation, platelet activation, coagulation, erythrocyte aggregation and hemolysis compared to branched cationic polyethyleneimine (PEI). The degree of quarternization does not have large influence on the blood compatibility of the new polymers. Cytotoxicity of these polymers is significantly lower than that of PEI and is a function of quarternized nitrogen present in the polymer. Also, these polymers bind DNA in the nanomolar range and are able to condense DNA to highly compact, stable, water soluble nanoparticles in the range of 60-80 nm. Gel electrophoresis studies showed that they form electroneutral complexes with DNA around N/P ratio 1 irrespective of the percentage of quarternization under the conditions studied.

Biocompatible Materials↗

Mechanical properties and decay resistance of wood-polymer composites prepared from fast growing species in Turkey.

Some mechanical properties of wood-polymer composites from maritime pine (Pinus pinaster Ait.) and poplar (Populus x. euramericana cv. I-214) wood were investigated. Three different monomers; styrene (ST), methyl methacrylate (MMA) and styrene/methyl methacrylate (ST/MMA) mixture were used in preparation of wood-polymer composites (WPCs). Full-loading (FL), half-loading (HL) and quarter-loading (QL) were used as polymer content levels. Untreated pine and pine-polymer composite samples were tested in compression strength parallel to grain and static bending strength. WPCs mechanical properties increased compared to untreated wood. The polymer had greater effect on the strengths of the ST/MMA treated pine than on the ST and MMA treated pine samples. Increasing of the mechanical properties should improve the structural competitiveness of WPCs made from fast growing-low density woods. Weight losses due to fungal attack for pine and poplar-polymer composites were also determined. Although polymers at full and half loading levels helped decreasing weight losses due to both fungi for each wood species, weight losses were still found to be higher.

Compressive Strength↗

Crosslinked carboxymethylchitosan-g-poly(acrylic acid) copolymer as a novel superabsorbent polymer.

A novel carboxymethylchitosan-g-poly(acrylic acid) (CMCTS-g-PAA) superabsorbent polymer was prepared through graft polymerization of acrylic acid onto the chain of carboxymethylchitosan and subsequent crosslinking. It was demonstrated by FTIR spectroscopy that acrylic acid had been graft polymerized with carboxymethylchitosan. The thermal stability of the polymer was characterized by thermogravimetric analysis. By studying the swelling ratio of the polymer synthesized under different conditions, optimization conditions were found for a polymer with the highest swelling ratio. The rate of water absorption of the polymer was high, and the swelling of the polymer fitted the process of first dynamics. The swelling ratio of the polymer was pH-dependent.

Absorption↗

Clay charge reversal effects on aqueous polymer sorption on lateritic soils.

The effects of charge reversal about the measured point of zero charge (pH(0) approximately 5.2) of untreated and treated Sete Lagoas lateritic soil of Brazil on aqueous polymer sorption was investigated. The polymers are anionic sodium carboxymethyl cellulose (CMCA), nonionic polyethylene oxide (PEO), and cationic polyacrylamide (PAM). They were prepared at aqueous concentrations and pH ranges of 0.1-2.0 g l(-1) and 2-9, respectively. Soil treatment involved the removal of iron oxides by treatment with dithionate-bicarbonate-citrate. Batch sorption test results show that the presence of iron oxides in lateritic soil tends to suppress sorption of CMCA (especially at pH=pH(0)) and PEO (for the whole pH range) but has uncertain effects on cationic PAM sorption. CMCA sorption on the untreated soil improves on either side of pH(0), in direct proportionality to solution concentration, except at pH<4.0, where disassociation of the polymer molecules may decrease sorption energy. Increase in the sorption of non-cationic polymers (CMCA and PEO) at pH>pH(0) is attributable to dispersion of clay, cation bridging and polymer molecular reconfiguration. For cationic PAM, electrostatic bonding to negatively charged soil particle surfaces accounts for the sorption increase. For treated soil samples, polymer sorption pattern is similar to those expected for the montmorillonitic clayey soils of temperate zones. These results indicate that the pH(0) of lateritic soils, within the regime that exists in the field, should be considered in assessing the potential effectiveness of polymer dust suppressants for tropical lateritic soils.

Acrylic Resins↗

A new method to determine the partial solubility parameters of polymers from intrinsic viscosity.

A modification of the extended Hansen method, formerly used to determine the partial solubility parameters of drugs and non-polymeric excipients is tested with a polymer for the first time. The proposed method relates the logarithm of the intrinsic viscosities of the polymer in a series of solvents and solvent mixtures with the Hansen (three parameter model) and Karger (four parameter model) partial solubility parameters. The viscosity of diluted solutions of hydroxypropyl methylcellulose (HPMC) was determined in pure solvents and binary mixtures of varying polarity. The intrinsic viscosity was obtained from the common intercept of the Huggins and Kraemer relationships. The intrinsic viscosity tends to increase with increasing the solubility parameter of the medium. The results show that hydrogen bonding and polarity of the polymer largely determine polymer-solvent interactions. The models proposed provided reasonable partial and total solubility parameters for the polymer and enable one to quantitatively characterize, for the first time, the Lewis acid-base ability of a polymer thus, providing a more realistic picture of hydrogen bonding for solvent selection/compatibility and to predict drug-polymer interactions. Combination of the dispersion and polar parameters into a single non-specific solubility parameter was also tested. The results extend earlier findings and suggest that the models are quite versatile and may be applied to drugs, non-polymeric and polymeric excipients.

Models, Chemical↗

Drug carrier systems based on water-soluble cationic beta-cyclodextrin polymers.

This study was designed to synthesize, characterize and investigate the drug inclusion property of a series of novel cationic beta-cyclodextrin polymers (CPbetaCDs). Proposed water-soluble polymers were synthesized from beta-cyclodextrin (beta-CD), epichlorohydrin (EP) and choline chloride (CC) through a one-step polymerization procedure by varying molar ratio of EP and CC to beta-CD. Physicochemical properties of the polymers were characterized with colloidal titration, nuclear magnetic resonance spectroscopy (NMR), gel permeation chromatography (GPC) and aqueous solubility determination. The formation of naproxen/CPbetaCDs inclusion complexes was confirmed by NMR and fourier transform infrared spectroscopy (FT-IR). Cationic beta-CD polymers showed better hemolytic activities than parent beta-CD and neutral beta-CD polymer in hemolysis test. The morphological study of erythrocytes revealed a cell membrane invagination induced by the cationic groups. The effects of molecular weight and charge density of the polymers on their inclusion and release performance of naproxen were also investigated through phase-solubility and dissolution studies. It was found that the cationic beta-CD polymers with high molecular weight or low charge density exhibited better drug inclusion and dissolution abilities.

Cyclodextrins↗