J. Kálal

Hydrogels in endovascular embolization. I. Spherical particles of poly(2-hydroxyethyl methacrylate) and their medico-biological properties

Spherical macroporous particles based on poly(2-hydroxyethyl methacrylate) with defined porosity, swelling and morphology have been developed, and are suitable for endovascular occlusion of various organs. Unlike cylindrical particles, spherical particles are specifically suited for transcatheteral introduction. The method chosen for the preparation of such particles was suspension radical polymerization, where the monomers were dissolved in a mixture of higher-boiling alcohols, and the solution dispersed in water. Physicochemical and medico-biological properties of spherical particles were examined. The residual amounts of monomers and other low-molecular compounds were checked; haematological analyses showed that the value 10(-5) g/g of the polymer was not toxic and contributed to an irreversible aggregation of thrombocytes. The occlusion effect in the vascular lumen was stable. The histomorphological results fully demonstrated the perfect biocompatibility of artificial spherical emboli. The latter met the requirements of application to clinical practice.

Hydrogels in endovascular embolization. III. Radiopaque spherical particles, their preparation and properties

The synthesis and properties of spherical radiopaque hydrogel particles designed for endovascular occlusion are reported. These particles were prepared by the hydroxyl acylation of low crosslinked poly (2-hydroxyethyl methacrylate) beads with a nontoxic radiopaque compound based on triiodobenzoic acid, without affecting their properties which are advantages in medical practice. The effect of the iodine content on the size of dry and swollen particles is discussed. It has been found that an iodine content of about 25-30 wt% is desirable in order to obtain an easily recognizable X-ray image. These particles make the immediate control of embolus application easy and enable periodical inspection of the polymer to check the successful blockage of the vessel. They also open up the method of endovascular occlusion to further improvement.

Methacrylate gels with epoxide groups as supports for immobilization of enzymes in pH range 3-12.

Glycidyl methacrylate gels are carriers suitable for attachment of enzymes and for use in affinity chromatography. Experiments on the coupling of glycyl-L-leucine and acetyl-L-leucine to these gels have shown a high pH-dependence of the bond formation between the support and the alpha-amino group (pH optimum 9.7); the coupling reaction between the epoxide group and the carboxyl group is practically pH-independent. Serum albumin and trypsin were attached to a greater extent in acidic than in alkaline media. The effects of time and temperature were also studied. The catalytic action of immobilized trypsin, as well as its use for affinity chromatography of trypsin inhibitor, were studied.

Hydrogels in endovascular embolization. II. Clinical use of spherical particles

In this study we report the results of clinical experiments, obtained with spherical particles made from poly(2-hydroxyethyl methacrylate) used in the embolization of arteriovenous anastomoses, in the suppression of pulmonary haemorrhage and haemoptysis and in the occlusion of some other arteries. So far we have used these particles in the treatment of 187 patients. It must be stressed that the advantage of spherical particles consists in the simplicity of their introduction into the blood vessel through a catheter, while in the blood vessel itself the particle swells in blood still more, when compared with the particle size in saline. This results in an immediate and permanent haemostatic effect. No revascularization occurs.

Reactive polymers : XXV. Morphology of polymeric sorbents based on glycidyl methacrylate copolymers☆

Abstract Scanning electron microscopy was used to obtain basic data on the surface and internal morphology of macroporous copolymers based on glycidyl esters of methacrylic acid which are useful as chromatographic sorbents. The basic morphological units in beads consist of spherical microparticles (globules and nodules), hundredths to tenths of a micrometre in size. On the bead surface the globules are compactly arranged in the shell, owing to the surface tension in suspension copolymerization. The pores in the shell are an order of magnitude smaller than the macropores between the aggregates of globules inside the beads. With increasing content of the crosslinking agent in copolymers, the microparticles become finer and more individualized, which explains the increase in the specific surface area of the sorbents. In gas chromatography, the morphology of the sorbent preferentially determines the retention of non-polar compounds, while that of polar compounds is affected by the chemical composition of copolymers, that is, by the content of glycidyl epoxy groups in this instance.

Reactive polymers : XV. polar polymeric sorbents based on glydicyl methoacrylate copolymers

Abstract The basic chromatographic characteristics of a number of copolymers based on glycidyl esters of methacrylic acid have been determined. The individual samples are characterized by a broad range of specific surface areas (44–434 m 2 /g) and polarities, which have been evaluated by means of modified Rohrschneider constants. The retention times of adsorbates on these poymeric sorbents are very short, though the selectivity of separation remains intact, so that they can be used at working temperatures similar to those used in gas—liquid chromatography.

Synthetic model polymers in the study of protein immobilization on glycidyl methacrylate carriers

Abstract The reactive polymer polysuccinimide was aminolysed with the spin label 2,2,6,6-tetramethyl 4-aminopiperidine- N -toxide to obtain on average about 9 unpaired spins/macromolecule. The remaining monomeric units were partially converted (80–99.5 mol%) to the 2-hydroxyethyl aspartamide residues, partly substituted with functional groups modelling side chains of natural proteins: carboxyl, primary alkylamine, imidazole, indole and 4-hydroxyphenyl groups. These model water-soluble polymers were reacted with the macroporous spherical carrier formed by glycidyl methacrylate-ethylene dimethacrylate copolymer and with epoxy-activated Sepharose. The amount of immobilized model compound was estimated by e.s.r. measurement. Reaction kinetics were studied at pH 3.85, 6.7, 8.15 and 9.55 at 4, 37 and 65°C. Flurescent amine was used to visualize the penetration of aqueous reactant solution into the beads. The binding yield of carboxyl-containing models was low at all pHs. Models with amine react easily and the binding yield at various pH values was clearly determined by dissociation. A rather different pH dependence was obtained with imidazole-containing models. The binding of 4-hydroxyphenyl and indole groups proceeded over the whole pH range, being highest on the acid side. Only a minor portion of binding groups accessible to low molecular weight reactants is occupied by the model polymers, even at saturation. The results suggest that with the synthetic carrier the kinetics of immobilization are dominated by diffusion of the reactant into the carrier particle followed by fast sorption on the internal surface which increases its local concentration in the vicinity of the oxirane reactive groups and which is responsible for the rapid onset of immobilization. The effect of sorption is almost absent with epoxy-activated Sepharose.

Reactive polymers—VII. Complexes of bivalent ions with reaction products of the copolymer glycidyl methacrylate-ethylene dimethacrylate with 2-hydroxyethyl, ethyl and diethyl amine

Abstract Reaction of the copolymer glycidyl methacrylate-ethylene dimethacrylate with ethyl amine, diethyl amine, and 2-hydroxyethyl amine were employed to prepare new types of macroporous complexing resins. Their reaction with Cu, Zn, Fe, Ni and Co was studied. The amount of the metal sorbed, as well as the selectivity of the resin, drops in all the polymer derivatives studied very remarkably in the above mentioned order. The selectivity coefficient for the reactions with Cu 2+ and Co 2+ ions was established. Measurement of the hydrolytic stability of the complexes led to the conclusion that, with respect to stereochemical requirements of the metal, different complexes were formed utilizing further —OH groups or water molecules contained in the resin. The existence of the complexes was also demonstrated by i.r. spectroscopy.

Effect of the nature of proteins on their coupling to different epoxide-containing supports

Abstract Quantities of serum albumin, papain, chymotrypsin, trypsin and polyvalent natural trypsin inhibitor antilysin coupled to 3-(2′,3′-epoxypropoxy)propyl-glass, 3-(2′,3′-epoxypropoxy)propyl-silica, epoxyactivated Sepharose 6B, glycidyl methacrylate copolymer and oxirane-acrylic beads (Rohm Pharma) were determined as a function of pH of the reaction mixture. Optimal coupling pH and the amounts of attached individual proteins were considerably affected by both the nature of the coupled protein and the nature of the solid matrix. In some cases the effect of increased ionic strength was studied. Differences in plots of the dependence of the amount of the coupled protein on pH and ionic strength are discussed in respect to the differences of isoelectric points, hydrophobicity and charge distribution of proteins and supports.

Investigation of the surface structure of polymers by chromatographic methods : V. Use of gel permeation chromatography in the study of the porous structure of copolymers of glycidyl methacrylate

Abstract Gel permeation chromatography (GPC) was used in an inversion function to characterize the porous structure of macroporous copolymers. Using macroporous glycidyl methacrylate copolymers as an example, the relationships between the exclusion limit in GPC and the pore size and porosity of the sorbent, the distribution coefficient and the pore geometry and size, and the peak widening and morphology of the porous structure were established. Characteristic quantities are compared with results provided by other methods, especially electron microscopy, mercury porosimetry and nitrogen sorption. It was demonstrated that the porous structures of strongly cross-linked macroporous copolymers in the swollen and dry states differ.