LEE- Tekstil Mühendisliği Lisansüstü Programı
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Yazar "Karakaş, Hale" ile LEE- Tekstil Mühendisliği Lisansüstü Programı'a göz atma
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ÖgeComposite nanofiber patches for topical drug delivery systems(Graduate School, 2021-04-19) Barbak, Zarife ; Karakaş, Hale ; 503122805 ; Textile Engineering ; Tekstil MühendisliğiNanofibers are ultrafine, continuous, solid state textile fibers that have diameters less than 1 micrometre. Nanofibers possess remarkable properties such as high interconnected porosity, specific surface area, ability to imitate the Extra Cellular Matrix (ECM) and potential carrier for drug delivery. Due to these fascinating properties, nanofibers are attractive candidates for medical applications for instance wound dressings, tissue scaffolds and artificial blood vessels. Electrospinning is the simplest and most practical among all methods to produce fine fibers with diameters ranging from micrometres to nanometres. Basic electrospinning equipment includes a high voltage source, a solution feeding unit, a syringe with a tip and a collector. At first, high voltage is applied to the polymer solution to produce an electrical field between the tip and the collector to shape the droplet on the tip as Taylor Cone. When the electrostatic force is higher than the surface tension of the polymer solution, polymer jet is ejected from the tip to the collector. Then, polymer jet reaches to collector following a spiral way by getting longer and thinner. Finally, nanoscale fibers are obtained on the collector. Topical drug delivery systems are composed of a formulation that applied to the skin directly to heal disorders or disease of the skin which guide/target pharmacological effect of the drug to the skin surface. Different pharmaceutical dosage forms can be used in topical drug delivery such as gels, creams, ointment, liquid preparation, sprays and solid powders. Electrospun nanofibers are excellent materials for drug delivery systems due to high interconnected porosity, high surface area, ability to imitate the Extra Cellular Matrix (ECM), potential carrier for drug delivery. Utilization of nanofibers in drug delivery systems is based on the principle that the high surface area of the nanofibrous formulation increases the dissolution rate of the drug. Compared with other dosage forms such as; liposomes, micelles and hydrogels, major advantages of nanofibers are increment in drug loading efficiency and loading capacity, low systemic toxicity and excellent stability. Furthermore, several drugs can be carried within nanofibers with high local drug concentration due to their excellent targeting and drug transportation ability in a safe way. Electrospinning offers the opportunity for direct loading of drugs or biological agents for instance antibacterial molecules, antibiotics, enzymes, growth factors, proteins, peptides, vitamins, DNA into the electrospun nanofibers. Poly (ε-caprolactone) (PCL), Poly Lactic Acid (PLA) and Poly (ethylene oxide) (PEO) were used as carrier polymers for drug delivery. PEO is a highly aqueous soluble polymer, that interacts with the body fluid quickly due to its hydrophilicity resulting in dissolution. PEO is widely used in the polymer matrix to enhance bioavailability and solubility of drugs because of its high aqueous solubility and unique properties in drug delivery applications. The compatibility of PCL and PLA with different types of drugs enables uniform drug distribution in the polymer matrix and the slow degradation rate makes them favourable for prolonged drug delivery systems. In recent years, various studies were reported on the fabrication of drug delivery systems, generated by electrospinning of PCL, PEO, PLA and their blends. PCL, PEO, PLA nanofibers or their blends were loaded with different drugs and biological agents such as; Niclosamide, Silver nanoparticles, Vitamin B12, Curcumin, Lysozyme, AgNO3, Metronidazole (MNA). Polymer blending is an effective approach to prepare functional nanofibers by incorporating the favourable properties of the component polymers. Furthermore, polymer blending facilitates the manipulation of physical, mechanical or biochemical properties of nanofibers. Hydrophilic/hydrophobic polymer blends have been electrospun into nanofibers to fabricate controlled DDS. The hydrophobic polymer forms the backbone structure and it degrades slowly, creating a long term but steady-state drug release. On the other hand, the hydrophilic polymer degrades with a more rapid process, faster than hydrophobic, which accelerates the drug release. In this study, hydrophilic water-soluble PEO was selected for the polymer matrix to enhance the solubility and bioavailability of insoluble SSD. The hydrophobic character of PCL and PLA offers a long period SSD release therefore hydrophilic PEO was blended with hydrophobic PCL and PLA. Thus, PCL/ PEO and PLA/PEO composite polymer matrix was used to provide both increased solubility and controlled release of SSD. Silver sulfadiazine (SSD) is a non-ionized, water-insoluble, topical agent with a wide range of antimicrobial activity that is affected both on bacteria and fungi. SSD is a sulfonamide based drug that is formed by the reaction of sulfadiazine with silver nitrate to form complex silver salt. SSD is used extensively in the topical treatment of infected burns. Silver sulfadiazine provides a long-term release of silver ions, whereas in the case of other silver salts, such as silver nitrate, large amounts of silver ions are released all at once. Thus, the use of SSD decreases the need for frequent application. This makes SSD a desirable and favourable agent since the frequent application is not always practical or possible for patients. However, the low aqueous solubility (3.4 mg/l at pH = 6.8) restricts the drug efficiency, bioavailability and potential antimicrobial activity of SSD thus its applications are limited. Drug solubility is an important issue since efficient drug release and antimicrobial efficiency is contributed just by decomposition of SSD to sulfadiazine and silver ions. Also, the solubility problem of SSD makes it difficult to be stabilized and incorporated into the polymer matrix. The aim of the thesis is to produce a novel SSD loaded topical drug delivery system by using advantages of electrospun nanofibers. Also, a new buffer, Water/Propylene Glycol/ Phosphoric Acid (82:16:2) was utilized to investigate the dissolution and release behaviour of SSD. Thereby SSD containing PCL/PEO and PLA/PEO composite nanofiber carriers were electrospun to achieve the enhancement in solubility, effective drug release and efficient drug loading of SSD. For this purpose, initially, the water-insoluble SSD was incorporated into highly aqueous soluble PEO to increase the solubility. Afterwards, the PEO+SSD solution was blended with PCL and PLA solution to produce composite PCL/(PEO+SSD) and PLA/(PEO+SSD) nanofibers and PCL/(PEO+SSD) casting films for topical drug delivery. SEM method was used to enable the observations of fiber defects and irregularities in the nanofibers structures and to measure the average fiber diameters of the nanofibers. The morphological characterization of the casting films was carried out by SEM and Optical Profilometer. Energy dispersive spectra (EDS) analysis was performed to confirm that the composite nanofibers and casting film which contain SSD, by detecting the Silver (Ag), Nitrogen (N), Sulphur (S) content of the nanofibers. Moreover, EDS-Mapping was carried out to show the distributions of these elements in the composite nanofibers and casting films. The stability of SSD in the fiber structure and the molecular interactions in the drug-free and drug loaded nanofibers were examined by Attenuated Total Reflectance Infrared (FTIR-ATR) Spectroscopy. The crystalline structure of the SSD loaded composite electrospun nanofibers were investigated with X-ray diffraction (XRD) analysis. Atomic Force Microscopy (AFM) was used to determine the surface roughness of the composite nanofibers. 3D AFM Images show the roughness structure of nanofibers. Water contact angle measurements were performed to evaluate the wettability properties of the fabricated nanofibers and casting films surfaces. In vitro drug release media and release conditions were optimized and the controlled drug release profile was obtained for 24 hours. Drug loading efficiency of the nanofiber formulations and casting film were calculated. To understand the SSD drug release mechanisms from SSD loaded formulations; Zero Order, First Order, Higuchi, Hixon Crowell and Korsmeyer-Peppas kinetics models were applied in the drug release profiles of the formulations. Drug release studies were also verified with conductivity measurement due to the conductive nature of SSD. Antibacterial activities of the composite nanofibers against gram-positive Staphylococcus aureus (S. aureus) and gram negative Pseudomonas Aeruginosa (P. aeruginosa) Escherichia coli (E. Coli) bacteria were performed for the period of 24, 48 and 72 hours according to disc diffusion test method. Also, the antibacterial activity of commercial SSD cream was tested for comparison with nanofiber formulations. Furthermore, antibacterial activity of the SSD loaded PCL/PEO and PLA/PEO nanofibers were examined with determining MIC and MBC values. Stability studies of the composite nanofibers were done for 3 and 6 months periods. Nanofiber samples were kept both at refrigerator conditions (+4ºC) and room conditions (25ºC ±2 and 65 % ±2ºC relative humidity) to evaluate stability of nanofiber patches. Stability tests were performed with calculating drug loading amount, cumulative drug release by UV absorption measurements and analysing surface morphology by SEM analysis. Finally, the cytotoxicity studies of the drug loaded and drug-free PCL/PEO and PLA/PEO nanofiber patches were done with using the cell viability assay (MTT assay).
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ÖgeElectrospun composite nanofibers with metal/metal oxidenanoparticles(Graduate School, 2021-04-21) Başkan, Havva ; Karakaş, Hale ; 503142809 ; Textile Engineering ; Tekstil MühendisliğiFunctional materials have taken great interest due to their superior physical and chemical features which allow them to be succesfully used in a wide range of engineering applications. Nanomaterials, specifically nanofibers are regarded as functional materials due the their high surface area to volume ratio, high pore interconnectivity, small pore dimensions and superior chemical and mechanical features. Nanofibers are produced by mainly electrospinning which is a simple and inexpensive technique. Moreover, many types of polymers or polymer blends can be converted to nanofibers by electrospinning. Combination of two or more materials in a nanofibrous structure can result in functional materials. In this thesis, the goal was obtaining functional nanofibrous materials by incorporating a noble metal (silver) and metal oxides (iron III oxide (Fe3O4) and aluminum oxide (Al2O3)) in novel polymeric nanofiber structures and evaluate the biological features of the samples for medical applications. First of all, a novel Poly (acrylonitrile-co-itaconic acid) (P (AN-co-IA)) copolymer was synthesized by emulsion polymerization. In the literature, copolymerization of itaconic acid (IA) with acrylonitrile (AN) was performed for decreasing the cyclization temperature of polyacrylonitrile (PAN) homopolymer and consuming less energy for carbon fiber production. However, in the scope of the thesis, it was aimed to enhance the application areas of IA by integration of metals and metal oxides. Since Fe3O4 nanoparticles and Al2O3 nanoparticles play an imperative role in many biomedical applications, they were utilized together with P (AN-co-IA) copolymer. It was very difficult to study with metal oxide nanoparticles due to their tendency to agglomeration. For that reason, the appropriate amount of metal oxide nanoparticles was determined first by using polyacrylonitrile /N,N Dimethylformamide (PAN/DMF) solutions. Afterwards, the optimized amout of Fe3O4/ Al2O3 nanoparticles were added into P (AN-co-IA)/DMF polymer solutions and the solutions were subjected to electrospinning to obtain a nanofibrous structure. In addition to conventional electrospinning, coaxial electrospinning was also performed for metal oxide nanoparticle incorporation. Detailed morphologic and spectroscopic characterizations of the obtained nanofibers were performed. Thermal features of the resultant nanofibers were also analyzed by Differential Scanning Calorimety (DSC) and Thermogravimetric Analysis (TGA). It was captured from the characterization results that addition of metal oxide nanoparticles to P (AN-co-IA) copolymer structure altered the features of the plain P (AN-co-IA) nanofibers. Even using very small amount (1 wt %) of Al2O3 caused improvements in thermal stability of the nanofibers. On the other side, silver nanoparticles (AgNPs) formation and integration to polymer structures were achieved by different chemical and physical methods. By the assistance of P (AN-co-IA) polymer and DMF, AgNPs were formed in-situ in polymer solution and then the polymer solution was electrospun for nanofiber production. The novelty of the method was related to the decreased reduction duration of silver nitrate (AgNO3) by using P (AN-co-IA) polymer. The method was compared with the literature studies on the utilization of PAN polymer for reduction of AgNO3. P (ANco-IA) polymer allowed to obtain AgNPs from the precursor AgNO3 two times faster than PAN. Moreover, it was understood that P(AN-co-IA)/Ag nanofibers had high electrical conductivity, enhanced thermal stability and satisfying nanofiber morphologies. Besides conventional electrospinning, AgNPs were introduced into P(AN-co-IA) polymer structure via coaxial electrospinning. In the process, AgNO3/DMF solution was prepared to be used as a shell solution and P (AN-co- IA)/DMF solution was prepared as a core solution. Since the most important point in coaxial electrospinning is the feed-rate of core and shell solutions, a set of experimental study was performed for the optimization of flow-rate (0.2 ml/h) of shell solution. After coaxial electrospinning, P(AN-co-IA)(core)/ AgNO3 (shell) nanofibers were subjected to UV-irradiation to generate AgNPs by the reduction of AgNO3. UVirradiation duration was optimized as 3 hours by using PAN(core)/ AgNO3 (shell) nanofibers. In addition to P (AN-co-IA) and PAN polymers, biodegradable and biocompatible poly (3-hydroxybutyrate) P (3HB) and poly (3-hydroxyoctanoate-3 hydroxydecanoate)(P (3HO-3HD)) polymers were also utilized for the combination of AgNPs. To this end, nanofibers of P (3HB)/P (3HO-3HD) were collected via conventional electrospinning and by dip-coating they were coated with AgNPs. As in the nanofibers including metal oxide nanoparticles, detailed morphologic, spectroscopic and thermal characterizations of the resultant nanofibers were performed by Scanning Electron Microscope –Energy Dispersive Spectroscopy (SEM-EDS), Ultra Violet-Visible (UV-Visible) and Fourier Transform Infrared-Attenuated Total Reflectance (FTIR-ATR) spectroscopy, and DSC. Most importantly, antimicrobial activity studies of P(AN-co-IA)/Ag nanofibers (obtained via conventional electrospinning) against S. aureus, E.coli, P. aeruginosa and C. albicans and immunomodulatory properties of P (3HB)/P (3HO-HD)/Ag nanofibers against special cytokines (IL-1 (α and β), IL-6, IL-8, TNF-α, TGF-β and HBD-2) were evaluated. Related to the antimicrobial activity results of P (AN-co-IA)/Ag nanofibers, it was observed that the nanofibers produced inhibition zones against the studied microorganisms. That was also proved by susceptibility testing. According to time-kill analysis, without silver nanoparticles, either PAN or P (AN-co-IA) nanofibers did not show any antimicrobial activity against any microorganisms. However, bacteriostatic/fungistatic activity was observed for all nanofiber samples which include AgNPs at almost all time points. Bactericidal activity was started from 24-48 hours and lasted until 120 hours at 10x Minimum Inhibitory Concentration (MIC) whereas fungicidal activity was observed between 120 and 168 hours at 10xMIC. Based on the real-time reverse transcriptase polymer chain reaction (RT-PCR) tests of P (3HB)/P (3HO-3HD)/Ag nanofibers, it was understood that while plain P(3HB)/P(3HO-3HD) nanofibers did not show any difference in the basal production of these molecules by HaCaT cells in culture, AgNP-containing P(3HB)/P(3HO-3HD) nanofibers upregulated the studied proinflammatory cytokines which were IL-1(α and β), IL-6 and IL-8 after 6 hours to start the healing process. Those findings of AgNPs containing P (AN-co-IA) and P (3HB)/P (3HO-3HD) nanofibers revealed that they could be used in wound dressing or tissue engineering applications effectively. Polypyrrole (PPy) is popular with its conductivity, but it can also be used in biological applications such as biosensors and drug delivery. However, due to the problems in processing with PPy, it is very difficult to obtain PPy nanofibers. In this thesis, it wasaimed to combine PPy with AgNPs to be used in biological applications and also converting it to a nanofibrous web structure by the help of P (AN-co-IA). Since it was difficult to electrospin P (AN-co-IA), PPy and AgNPs in a single step, AgPPy was synthesized via chemical oxidation polymerization first. Then AgPPy and P (AN-co-IA) was gathered in a nanofiber structure via coaxial electrospinning. AgPPy/DMF solution was prepared as shell solution and P (AN-co-IA) /DMF was prepared as core solution. It can be fairly said that the same protocol of the abovementioned coaxial electrospinning was performed for coaxial electrospinning of P (AN-co-IA) (core)/AgPPy (shell) nanofibers. Bead-free and continuous nanofiber morphologies with fine nanofiber diameters could be obtained. As a conclusion, in the scope of this thesis, functional nanofibers were achieved by incorporating metal/metal oxide nanoparticles into polymeric nanofiber structures with various experimental procedures. The obtained nanofibers are good candidates for medical applications where conductivity and antimicrobial activity are desired.