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Transdermal and subcutaneous drug delivery routes offer many advantages compared to the enteral route of drug administration including improved drug bioavailability, maintenance of optimal drug levels in the systemic circulation, reduction of toxicity, and better patient compliance. The overall aim of this dissertation was to synthesize and characterize composite hydrogels composed of the cross-linked poly(acrylic acid) hydrogel and the hydrophobic polymer base that are suitable for the storage and controlled delivery of cationic drugs mediated by non-specific electrical interactions. We successfully synthesized composite hydrogel membranes and implants by combining the ultraviolet or gamma irradiation-induced polymerization and liquid phase inversion. Physicochemical properties of the materials, such as chemical composition, microstructure, ion-exchange capacity, swelling behavior, and ionic conductivity, were analyzed. In vitro release from composite hydrogel reservoirs was investigated using methylene blue as the model drug. Examined composite hydrogel reservoirs showed mainly diffusion-controlled release kinetics. We developed a modeling approach based on the analytical solution for diffusion and the empirical Weber-Morris model that effectively describes the release kinetics using the concept of apparent diffusion coefficient. Rate-limiting barriers defined by the composite hydrogel microstructure and ion exchange governed the passive release kinetics. Iontophoretic excitation of composite membranes confirmed their electrical responsivity and induced an effective increase in the apparent diffusion coefficient. Obtained composite hydrogels hold promise for drug delivery, but also for applications in nanomaterial synthesis and iontronics. Transdermalni i subkutani načini dostave aktivnih supstanci nude brojne prednosti u poređenju sa enteralnim načinom jer se postiže veća bioraspoloživost leka, njegova optimalna koncentracija u sistemskoj cirkulaciji, smanjena toksičnost i veća komfornost pacijenata. Glavni cilj ove disertacije bila je sinteza i karakterizacija kompozitnih hidrogelova koji sadrže umreženi hidrogel poli(akrilne kiseline) i hidrofobnu polimernu bazu, a pogodni su za skladištenje i kontrolisanu dostavu katjonskih lekova putem nespecifičnih električnih interakcija. Kompozitni hidrogelovi, u formi membrana i implantata, su uspešno sintetisani kombinovanjem metoda polimerizacije indukovane ultraljubičastim ili gama zračenjem i metode mokre fazne inverzije. Analizirana su fizičko-hemijska svojstva materijala kao što su hemijski sastav, mikrostruktura, jonoizmenjivački kapacitet, karakteristike bubrenja i jonska provodljivost. Proces otpuštanja aktivne supstance iz kompozitnih rezervoara sa hidrogelom je ispitivan u in vitro uslovima korišćenjem metilenskog plavog kao model leka. Ispitani kompozitni rezervoari sa hidrogelom su pokazali uglavnom difuziono kontrolisanu kinetiku otpuštanja. Razvijen je pristup modelovanju zasnovan na analitičkom rešenju za difuziju i empirijskom Veber-Moris modelu koji efektivno opisuje kinetiku otpuštanja korišćenjem koncepta prividnog koeficijenta difuzije. Kinetika pasivnog otpuštanja je bila diktirana barijerama definisanim mikrostrukturom kompozitnog hidrogela i jonskom izmenom. Jontoforetska pobuda kompozitnih membrana potvrdila je njihovu elektroresponzivnost i indukovala efektivni porast prividnog koeficijenta difuzije. Očekuje se da dobijeni kompozitni hidrogelovi pronađu primenu u dostavi lekova, kao i u sintezi nanomaterijala i jontronici.

Nanostructured zinc oxides are promising materials for numerous biomedical applications where they can serve as therapeutic agents or tools for sensing and imaging. Despite their favorable properties, wider use of zinc oxide nanoparticles in biomedicine is limited by toxicity issues. Therefore, new synthesis approaches should be devised to obtain zinc oxide nanoparticles which are safe-by-design. We present an innovative low-cost wet precipitation synthesis of gelatin modified zinc oxide nanoparticles at the gel/liquid interface. The diffusion of ammonia through the gelatin hydrogels of different porosities induces precipitation of the product in contact with the surface of the aqueous solution of zinc ions. After thermal treatment of the precipitate, adsorbed organic residues of decomposed gelatin act as modifiers of zinc oxide nanoparticles. We characterized the physicochemical properties of obtained gelatin modified zinc oxide nanoparticles by XRD, FTIR, DTA/TG, and SEM. The synthesized nanoparticles show hexagonal wurtzite structure and form flakelike aggregates. FTIR and DTA/TG analyses indicate that the thermal decomposition of adsorbed gelatin depends on the gelatin content of the hydrogel used in the synthesis. We also examined the viability of HepG2 cells, generation of intracellular reactive oxygen species, and genotoxicity using the MTS, DCFH-DA, and alkaline comet assay, respectively. Fabricated gelatin modified zinc oxide nanoparticles show very low toxicity potential at doses relevant for human exposure.

Nanotechnology has great potential in the biomedical field. Among other nanomaterials, inorganic nanoparticles have become extremely important since they possess unique physicochemical properties influenced by their specific surface structure. Consequently, inorganic nanoparticles exhibit enhanced functionalities such as biological response, antibacterial and antiviral properties, as well as optical, magnetic, and electrical responses. They have found applications in medicine, pharmacy, controlled drug delivery, optics, electronics, etc. In this chapter, reports on obtaining different metallic and ceramic inorganic nanoparticles such as gold, silver, selenium, copper, iron, zinc oxide, and hydroxyapatite for biomedical applications will be addressed. For each of these nanosystems, the main challenges regarding the currently achieved functional properties and further perspectives will also be presented.

Composite implants comprising a biodegradable hydrophobic polymer matrix and crosslinked hydrogel with fixed ion exchange groups are promising materials for the construction of controlled drug delivery systems. Poly(lactic-co-glycolic acid)/poly(acrylic acid) (PLGA/PAA) composite implants in our study were synthesized using the sequential application of irradiation and immersion precipitation. Precursor solutions with all functional components were dispensed into a disc-shaped non-stick mold and cured either by ultraviolet (UV) or gamma irradiation. Cured disks were subsequently immersed in the phosphate buffer saline bath to finalize phase separation and solidification of the implants. The synthesized implants were characterized by FTIR-ATR and DSC, and their basic properties such as ion exchange capacity, swelling degree, and swelling kinetics were examined. Synthesis using gamma irradiation resulted in implants with similar ion exchange capacity, but the greater swelling degree and faster swelling kinetics compared to the implants prepared with UV irradiation. Gamma irradiation also resulted in altered and less homogeneous chemical composition compared to the implants synthesized with UV irradiation. Further investigations are required to determine the differences in drug release kinetics and degradation behavior of the synthesized implants.

Composites of biodegradable polymers and hydrogels are promising materials for controlled delivery systems with prolonged drug release. In this contribution, we present an innovative implant design comprising poly(DL-lactide-co-ε-caprolactone) copolymer base and a crosslinked poly(acrylic acid) hydrogel. Implants were prepared in the form of disks using the modified traditional liquid phase inversion process. Solutions containing all implant precursors were dispensed into transparent non-stick molds and cured by UV irradiation. UV curing was followed by immersion into the phosphate buffer solution bath to achieve phase separation and solidification. Structure and composition of the implant were characterized using SEM and FTIR. Obtained implants exhibited high loading capacity for cationic formulations and a moderate degree of swelling. Studies of implant loading and subsequent release of methylene blue into the phosphate-buffered saline demonstrated diffusioncontrolled delivery kinetics over a period of several weeks. To assess biocompatibility of implants as possible materials for drug delivery systems in mammals, we evaluated their effects on viability (Trypan blue exclusion assay), metabolic activity, proliferation (MTT assay) and priming (nitric oxide/NO production) of freshly isolated rat splenocytes during 24 h and 48 h of cultivation. The viability was unaltered, metabolic activity/proliferation was increased after 48 h and the decrease of NO production, as well as drop in responsiveness to cell mitogen concanavalin A (ConA) in cells on implants were observed. These results suggest that implants could be used as a suitable material for drug delivery systems, but their capacity to stimulate cell proliferation and their immunosuppressive potential deserve further investigations.

Polymeric pH-sensitive membranes and hydrogels are interesting materials for the controlled delivery of chemical agents triggered by external stimuli. In this contribution, we present a novel membrane design consisting of a polyethersulfone polymeric base and a crosslinked poly(acrylic acid) hydrogel containing pH-responsive carboxyl groups. Membranes were prepared using the modified traditional liquid phase inversion process. Solutions containing all membrane precursors were cast on a glass plate and cured by UV irradiation. UV curing was followed by immersion into the water bath to achieve phase separation and solidification. Obtained membranes exhibited high ion-exchange capacity and a moderate swelling degree dependent on the crosslinker properties. Studies of membrane loading with methylene blue and subsequent release of methylene blue from the membrane into the alkaline and acidic buffered solutions demonstrated pH-dependent delivery kinetics.

Building of laboratory hardware in-house can reduce overall equipment costs and respond to the specific requirements of the experiment. The aim of this contribution is to present the novel design and implementation of the low-cost module for AC electric excitation of chemical systems, mainly intended for modifying wet chemical synthesis of nanomaterials. Results of preliminary modelling and experimental tests indicate good module reliability and applicability of the modification methodology on various material types (ceramics, metals and proteins). Possible underlying mechanisms correlating the influence of alternating electric fields and material properties, as well as potential improvements in module construction are discussed.