Janusz M. Rosiak

Hydrogels and their medical applications

Abstract Biomaterials play a key role in most approaches for engineering tissues as substitutes for functional replacement, for components of devices related to therapy and diagnosis, for drug delivery systems and supportive scaffolds for guided tissue growth. Modern biomaterials could be composed of various components, e.g. metals, ceramics, natural tissues, polymers. In this last group, the hydrogels, hydrophilic polymeric gels with requested biocompatibility and designed interaction with living surrounding seem to be one of the most promising group of biomaterials. Especially, if they are formed by means of ionizing radiation. In early 1950s, the pioneers of the radiation chemistry of polymers began some experiments with radiation crosslinking of hydrophilic polymers. However, hydrogels were analyzed mainly from the point of view of the phenomenon associated with radiation synthesis, with topology of network and relation between radiation parameters of the processes. Fundamental monographs on radiation polymer physics and chemistry written by A. Charlesby (Atomic Radition and polymers, Pergamon Press, Oxford, 1960) and A. Chapiro (Radiation Chemistry of Polymeric Systems, Interscience, New York, 1962) proceed from this time. The noticeable interest in the application of radiation techniques to obtain hydrogels for biomedical purposes began in the late sixties as a result of the papers and patents invented by Japanese and American scientists, headed by Kaetsu in Japan and Hoffman in USA. Immobilization of biologically active species in hydrogel matrices, their use as drug delivery systems and enzyme traps as well as the modification of material surfaces to improve biocompatibility and their ability to bond antigens and antibodies had been the main subjects of these investigations. In this article a brief summary of investigations on mechanism and kinetics of radiation formation of hydrogels as well as some examples of commercialized hydrogel biomaterials have been presented.

Synthesis of hydrogels by irradiation of polymers in aqueous solution

Abstract Radiation methods used to obtain hydrogels for biomedical applications are briefly discussed. The method based on the irradiation of polymers in aqueous solution is dealt with in some detail. The importance of basic studies on the involved processes is emphasized. Some aspects of the radiation chemistry of polymers in aqueous solutions are discussed (e.g. the factors influencing the competition between the intermolecular crosslinking and other reactions), basing mainly on the data obtained by the authors’ research group.

Radiation formation of hydrogels for biomedical purposes. Some remarks and comments

Abstract Formation of hydrogels by means of radiation technique is described and some differences connected with irradiation in solid state and solution are pointed out. Structures of primary macroeradicals of some hydrophillic polymers are given. Examples of applications of hydrogels as drug delivery systems, implants, injectable systems, stimuli-responsive systems, hybrid-type organs as well as general requirements for such systems are reviewed. Hydrogel wound dressings produced by radiation technology and marketed in the Central Europe are described.

Medical applications of radiation formed hydrogels

Abstract Polyvinylpyrrolidone was used as a main component of two new biomaterials: hydrogels wound dressings and therapeutic system for induction of labour. Ionizing radiation was applied as a tool for initiation of crosslinking and sterilization of these materials. Both products successfully passed clinical tests and have been commercialized. Draft of technology and some properties are shortly reviewed in this report.

Radiation formation of hydrogels for drug delivery

Abstract Using N- vinylpyrrolidone as polymer of choice, it has been pointed out that radiation formation of hydrogels in aqueous solutions proceeds according to the radical mechanism. Both in the processes of polymerization and crosslinking, the main role is played by indirect effect, i.e., these processes are initiated by intermediate products of radiolysis of water. In the presence of oxygen in the irradiated solutions, the process of gel formation is accompanied by the reactions leading to the scission of polymer main chain. Analysing the course of gel formation the use of modified Charlesby equation was suggested. This equation has an universal character. In order to calculate the values of the yield of radiation crosslinking a new method was used. It allows to obtain results without previous determination of the molecular weights of polymer to be crosslinked.

Polymer gel water equivalence and relative energy response with emphasis on low photon energy dosimetry in brachytherapy.

The water equivalence and stable relative energy response of polymer gel dosimeters are usually taken for granted in the relatively high x-ray energy range of external beam radiotherapy based on qualitative indices such as mass and electron density and effective atomic number. However, these favourable dosimetric characteristics are questionable in the energy range of interest to brachytherapy especially in the case of lower energy photon sources such as 103Pd and 125I that are currently utilized. In this work, six representative polymer gel formulations as well as the most commonly used experimental set-up of a LiF TLD detector-solid water phantom are discussed on the basis of mass attenuation and energy absorption coefficients calculated in the energy range of 10 keV-10 MeV with regard to their water equivalence as a phantom and detector material. The discussion is also supported by Monte Carlo simulation results. It is found that water equivalence of polymer gel dosimeters is sustained for photon energies down to about 60 keV and no corrections are needed for polymer gel dosimetry of 169Yb or 192Ir sources. For 125I and 103Pd sources, however, a correction that is source-distance dependent is required. Appropriate Monte Carlo results show that at the dosimetric reference distance of 1 cm from a source, these corrections are of the order of 3% for 125I and 2% for 103Pd. These have to be compared with corresponding corrections of up to 35% for 125I and 103Pd and up to 15% even for the 169Yb energies for the experimental set-up of the LiF TLD detector-solid water phantom.

Radiation formation of polymeric nanogels

Abstract An alternative method of synthesis of polymeric nanogels is proposed, based not on polymerization, but on intramolecular crosslinking of polymer chains, initiated by pulse irradiation in dilute aqueous solutions. Kinetic data show that for many water-soluble polymers irradiation under these conditions result in intramolecular crosslinking. Preliminary product studies on poly(vinyl alcohol) indicate that in fact internally crosslinked macromolecules can be obtained by this technique.

Synthesis of poly(acrylic acid) nanogels by preparative pulse radiolysis

Abstract Nanogels are sub-micron size, water-swellable crosslinked structures of hydrophilic polymers. In this work a radiation-based synthesis method that has been previously tested for neutral polymers is applied for production of nanogels of a synthetic polyelectrolyte—poly(acrylic acid) (PAA). In this technique dilute, deoxygenated PAA solution (pH 2) circulating in a closed loop is subjected to pulse irradiation with fast electrons. In each pulse many tens of radicals are instantaneously formed on every macromolecule. One of the major reaction paths of these radicals is intramolecular recombination leading to the formation of nanogels. It is demonstrated that radiation-induced reactions in our system show a typical feature of intramolecular crosslinking, i.e . a strong decrease in dimensions of a polymer coil without an accompanying decrease in molecular weight. In accordance with expectations based on earlier observations on non-polar polymers, intramolecular recombination of PAA-derived radicals proceeds according to non-classical kinetics. A model of non-homogeneous kinetics with time-dependent rate constant has been applied to describe this behaviour and the relationship between kinetic parameters and initial average number of radicals per chain is briefly discussed. The weight-average molecular weight of the products is influenced by side reactions, mainly degradation (chain breakage) and intermolecular crosslinking.

THE USE OF RADIATION TECHNIQUE IN THE SYNTHESIS OF POLYMERIC NANOGELS

Abstract Irradiation of dilute, deoxygenated aqueous solutions of hydrophilic polymers with high-dose pulses of fast electrons leads to the simultaneous formation of many radicals on each polymer chain. These radicals undergo mainly intramolecular recombination. In this way internally crosslinked macromolecules – nanogels – are formed. Current data on poly(vinyl pyrrolidone) show that during this process the weight-average molecular weight remains almost constant, but there is a pronounced decrease in the radius of gyration of macromolecules, an effect expected for the formation of compact, internally crosslinked structures.

Nano-, micro- and macroscopic hydrogels synthesized by radiation technique

Radiation techniques, due to the additive-free initiation and easy process control, are very suitable tools for synthesis of biomaterials, especially hydrogels. In our group, a number of techniques have been elaborated allowing for targeted synthesis of gels of various size ranges, from internally crosslinked individual macromolecules, via microgels to macroscopic hydrogels. An example of a mature technology of this kind are hydrogel wound dressings, being now produced on large scale in Poland and other countries. Current research projects include: hydrogel-based system for anticancer therapy due to local drug delivery, systems for encapsulation of living cells, new approach to the synthesis of polymeric material for intervertebral discs implant, temperature-sensitive membranes, hydrogel phantoms of 3D radiation dosimeter for radiotherapy, degradation-resistant nanogels and microgels for biomedical purposes (e.g. synovial fluid substitute), hydrogel-based dietary products and adjustment of the molecular weight of biopolymers.