Investigation of swelling, drug release and mechanical properties of modified n-isopropylacrylamide based composite hydrogels

N-isopropylacrylamide (NIPAAm) is one of the monomers commonly used in temperature-sensitive linear and / or crosslinked polymer synthesis. In this study, several modifications were made to improve the properties of conventional poly(N-isopropylacrylamide) (PNIPAAm) hydrogels (gNH), such as altering/improving the mechanical properties, swelling, drug release and biocompatibility. These modifications are (i) the use of 0.1N and 0.2N NaOH solutions instead of distilled deionized water (DDS), which is often used in gNH synthesis as the polymerization solvent (modified conventional PNIPAAm hydrogels:mgNH), (ii) the use of inorganic multilayer smectites such as laponite (LP), Na-montorillonite (MMT) and octadecylamine montmorillonite (ODA-MMT) instead of N,N'-methylene bisacrylamide (BIS) as cross-linker (modified composite PNIPAAm hydrogels:mkNH) (iii) the use of 0.1N and 0.2N NaOH solutions as synthesis solvent and dispersion medium of the and layered silicates also function as polymerization accelerators thus removing the polymerization accelerator component (N, N, N ', N'-tetramethyl ethylenediamine- TEMED), which has frequently been used in the synthesis of conventional PNIPAAm hydrogels, from the reaction medium (iv) synthesis of modified conventional (mgkNH) and modified composite (mkkNH) PNIPAAm copolymer hydrogels using cationic and zwitterionic comonomers (modified conventional copolymer PNIPAAm hydrogels:mgkNH and modified composite copolymer PNIPAAm hydrogels:mkkNH) and (v) synthesis of mkkNHs in the form of modified full-IPNs in which sufficient modification/improvement of mechanical properties can not be provided (modified full-IPN copolymer PNIPAAm hydrogels:m(IPN)kNH). In summary, hydrogel syntheses in this thesis have been carried out in an environment in which polymerisation accelerator and organic cross-linker molecule are not present, the minimum number of organic components that may be present in the synthesis medium are present, and conditions providing the highest biocompatibility are created. As a result of these modifications, the properties of mgNH, mkNH, mgkNH, mkkNH and m(IPN)kNHs (a) compression moduli obtained from uniaxial compression tests between 30o- 45oC (b) V/Vo values calculated from the diameter and height measurements of hydrogel disks in the same temperature range (c) structural and morphological properties determined by XRD, FTIR, SEM-EDS and conductometric titrations (d) blood compatibility (e) antibacterial activities against E. coli (f) dynamic swelling behavior in PBS (pH 7.4) (g) pH dependent volumetric swelling (pH 2.0, 4.0, 6.0, 8.11, 9.20, 10.74 and 11.66) and (h) Gentamicin (GS) release properties were examined. In this study, the effects of the polymerization time on the material properties of the modified PNIPAAm hydrogels were also investigated. In particular, the increase in the compression modulus values of composite hydrogels due to the duration of the synthesis has shown that the polymerization reactions continue for two weeks depending on the polymerization conditions. In this thesis study, in order to see whether the 0.1N and 0.2N NaOH solutions preferred as polymerization medium and the long polymerization times have hydrolysing effect on NIPAAm-based hydrogels, conductometric titrations were made with selected hydrogel samples. The presence of a -COOH group of 0.66 mol% was found in the PNIPAAm/BIS hydrogel synthesized in the presence of TEMED and in 24 hours polymerization, which can be regarded as a control hydrogel. In hydrogel samples synthesized in the 0.1 and 0.2N NaOH solutions for 2 weeks -COOH group of 0.69-0.88 mol% was found. The obtained comparative findings have shown that the percentage of hydrolysis in mgNHs synthesized in 0.1N and 0.2N NaOH solutions and maximum reaction times of two weeks is not different from the conventional PNIPAAm hydrogels. Conductometric titration results with mkNHs also gave similar findings. XRD and FTIR analyzes of conventional and composite hydrogels and clay samples treated with 0.1N and 0.2N NaOH solutions were performed. The effects of alkaline polymerization medium on the structural properties of the crosslinkers and composite hydrogels were examined and the existence of basic functional groups such as amide, hydroxyl, isopropyl and silanol (in composite hydrogels) in NIPAAm based networks were proved. Two of the most striking features of the hydrogels used in the synthesis of biocompatible materials are their mechanical properties and their ability to compete with living tissues for hydrophilicity. In this thesis study, 0.1N and 0.2N NaOH solutions were used as the polymerization medium for hydrogel synthesis, besides DDS, different from literature studies. In this study, we have found that the synthesis conditions of 0.1N NaOH maintain the swelling capacity of the hydrogels and provide significant improvement in the compression modulus values in the range of 30o-45oC. It has been found that inorganic multifunctional smectites, which are used as crosslinkers at a ratio of 10% by weight with respect to NIPAAm (in mkNH and mkkNH), change the compression modulus values of the hydrogels depending on the synthesis conditions, increase the flexibility and durability and strengthen the hydrophilic characteristics of the materials. PNIPAAm / DMAPMAAm, which is flexible and brittle, has become hard and durable as the cross-linking component being changed from BIS to ODA-MMT. Particularly, in the PNIPAAm homopolymer and copolymer hydrogels in which the ODA-MMT was used, the elastic modulus values at the physiological temperature of 37oC, which reached the highest values in the examined temperature range, were also obtained. Another of the main objectives of this thesis study is to impart antibacterial activity along with pH sensitivity to modified traditional and composite PNIPAAmhydrogels. Three different comonomers that resemble NIPAAm (the key component in the molecular structure) have been used in the synthesis of the modified PNIPAAm hydrogels of the conventional and composite copolymers; N-[3-(dimethylamino)propyl]methacrylamide (DMAPMAAm), 3-(methacrylamino) propyl trimethylammonium chloride (MAPTAC) ve N,N-dimethyl-N-(3-methacrylamidopropyl)-N-(3-sulfopropyl) ammonium betaine (SBMAAm). In the data obtained from uniaxial compression tests of mgNHs and mkNHs, the polymerization medium for the synthesis of copolymer hydrogels was determined to be 0.1N NaOH and the polymerization time was one week. mgkNHs were synthesized using BIS as crosslinker and mkkNHs were synthesized using ODA-MMT. In order to improve the mechanical properties of the PNIPAAm/MAPTAC and PNIPAAm/SBMAAm composite hydrogels, which have lower moduli than the BIS cross-linked equivalents, (m(IPN)kNH) hydrogels have also been synthesized. m(IPN)kNHs uniaxial compression tests show that (i) the initial modulus value of PNIPAAm/DMAPMAAm IPN hydrogel is between conventional and composite PNIPAAm/DMAPMAAm hydrogels, whereas the flexibility and strength is significantly higher in IPN hydrogel (ii) the initial module value of PNIPAAm/SBMAAm IPN hydrogel was lower than that of conventional and composite SBMAAm hydrogels but that IPN hydrogel had much higher strength than conventional and composite PNIPAAm/SBMAAm hydrogels and (iii) in the PNIPAAm/MAPTAC IPN hydrogels, the initial module values were lower than the conventional PNIPAAm/MAPTAC hydrogel. Dynamic swelling behaviors in PBS at room temperature, swelling behavior at pH 30 (pH 2-12), and drug release behavior in physiological conditions (37oC and pH 7.4) were also investigated in the samples selected from the synthesized hydrogels. Dynamic swelling behaviors and drug release mechanisms of hydrogels have been determined using the Korsmayer-Peppas model, the zeroth order, the first order, Hixon-Crowell and Higuchi half (empirical) emission models and kinetic equations. Possible bactericidal properties of copolymer hydrogels containing strongly cationic MAPTAC and pH-depending ionic DMAPMAAm at 2.5% by mol were investigated against E. coli by the agar disk diffusion method (modified Kirby-Bauer disc diffusion method). The drug release properties and antibacterial properties of selected hydrogels were examined by UV-Vis spectroscopy and agar disc diffusion method, respectively, using Gentamycin, an effective antibiotic, especially on gram negative bacteria strains. Disk diffusion test results show that the inhibition zone diameters generated by gentamicin loaded hydrogel discs are associated with module values at 37oC. It has been observed that conventional copolymer hydrogels synthesized in DDS and 0.1N NaOH media have lower modulus values and wider inhibition areas than conventional homopolymer hydrogels (BIS/0/1 and BIS/0.1/1). Hemolytic activities of conventional and composite homopolymer PNIPAAm hydrogels at concentrations of 1 mg/ml and 5 mg/ml and ODA-MMT samples treated with 0.1 N NaOH solution were investigated using healthy human erythrocytes as a biological membrane system. After incubation for 180 minutes at 37oC % haemolysis rates of erythrocytes in contact with hydrogel specimens were calculated using absorbance values determined by UV-visible spectrophotometer. The results showed that, for the mgNH, mkNH, mgkNH, mkkNH ve m(IPN)kNH specimens studied, hemolysis rates were below 5%, the highest acceptable hemolysis level for polymeric materials with blood compatibility. The hydrogels synthesized within the scope of the study are important starting points for the development of materials with high biocompatibility to be used in the biomedical field, especially those with improved module and strength at physiological temperatures.