Designing and mathematical modeling of pH responsive biopolymer hydrogels for targeted drug delivery in controlled release systemsKopač, Tilen (Avtor) Ručigaj, Aleš (Mentor) hydrogelrheologycrosslink densitypolymer interactionscontrolled drug releasemathematical modellingTargeted drug delivery to the desired site and controlled release rate increase treatment efficacy, reduce side effects and patient burden, protect the drug from degrading factors in the body, and reduce treatment costs. In this field, hydrogels are most commonly used as drug delivery systems. Fabrication and design of appropriate hydrogel properties to encapsulate and protect the drug, transport it to the desired location, and changing the structure of the hydrogel to cause drug release at a specific rate requires a series of complex studies and experiments. In this dissertation, mathematical modeling of hydrogel properties is presented to predict key parameters for designing the desired properties of hydrogels, such as shear modulus, crosslink density, mesh size, and drug release rate. The proposed approach could be useful in all hydrogel applications where the design of desired hydrogel properties is crucial. The developed mathematical model could reduce the number of experiments required for hydrogel development, thereby shortening research time, reducing research costs, and reducing the consumption of chemicals and energy, contributing to more environmentally friendly research. The polymer concentration, the mass fraction of polymers in the mixture, and the concentration and type of crosslinking agent are crucial when designing hydrogels with desired properties. For the purpose of targeted delivery and biocompatibility, pH-sensitive biopolymers were used. Hydrogels were prepared from modified nanocellulose, alginate, and scleroglucan, which represent the biopolymeric base of the systems studied. In order to extend the pH range of the hydrogels, the cationic functionalization of cellulose nanofibrils was carried out to extend the number of pH-responsive biopolymers. The research area was complemented by the preparation of hydrogels from different blends of basic biopolymers, expanding the possibilities to design the properties of the hydrogel network (mesh size, charge, hydrophilicity) to meet the requirements of a wide range of applications. The final part of the network modification was the use of the rheological modifier Laponite, which was incorporated into the network to influence the barrier properties of the hydrogel. Additional control over the crosslink density and thus the mesh size was achieved by using a crosslinking agent. In most cases, ionic crosslinkers such as calcium ions were used to maintain biocompatibility. Mathematical modeling of the drug release technology involves a detailed analysis of two key mechanisms, namely diffusion and the kinetics of adsorption and desorption of the drug in the case of electrostatic interactions with the hydrogel surface. The mass transfer by diffusion is directly related to the mesh sizes, as they allow complete encapsulation of the drug when the hydrodynamic radius of the drug is larger than the mesh size. On the other hand, increasing the mesh size allows diffusion of the drug. The release rate can be controlled by adjusting the mesh size, which acts as steric barrier. Therefore, the first part of the dissertation aims to develop a mathematical model to predict the mesh size in a hydrogel network as a function of the concentration of biopolymers and crosslinking agents. The mesh size was determined by oscillatory rheology measurements. The mechanical properties of hydrogels determine the shear modulus and crosslink density, which are the most important parameters for determining mesh size. In the dissertation, the theory of polymer-polymer interactions was introduced, which allows the analysis of the mechanical properties of hydrogels as a consequence of the interactions between the polymer chains that occur during the crosslinking process. In addition, the crosslink density was defined as the number of interactions between the polymer chains per hydrogel volume. It was shown that the number of bonds formed during crosslinking depends on the concentration of functional groups on the polymer surface, the concentration of the polymer and the crosslinking agent, and the tendency to form interactions between the polymer chains. Based on the observed predominant effect of hydrogen and ionic interactions, we developed a generalized mathematical model to predict the shear modulus, crosslink density, and mesh size in the hydrogel as a function of polymer and crosslinking agent concentration. The model was further modified to respond to hydrogels in an environment with different pH and temperature values. Using the developed model in already known correlations between mesh size and diffusion coefficient, the drug release rate was predicted in cases where diffusion is the predominant transport phenomenon and drugs do not form interactions with hydrogels. The model was verified by numerous release tests in a medium with different pH and temperature. Theophylline and FITC-dextran with different molecular weights were used as modeldrugs. In this way, the effect of the size of the drug (hydrodynamic radius) on the release rate was also mathematically evaluated. The second part of the dissertation deals with the comprehensive characterization of hydrogels and the search for material properties that influence the design of hydrogels as drug delivery systems. In addition to the rotational oscillation measurements mentioned earlier, rheological rotation tests with continuous rotation were performed, which are particularly important from the point of view of the application properties of hydrogels. A comprehensive study of various hydrogel systems based on biopolymer blends with the addition of Laponite as a rheological modifier was published. Detailed analysis of flow behavior and determination of zero-shear viscosities and yield stresses led to the exploration of the direct relationship between mechanical and flow properties. This study also allowed us to modify the mathematical model for predicting crosslink density with a correlation factor so that we could also mathematically predict the yield stress of hydrogels. The approach to determine the correlation between mechanical and flow properties has led to a better understanding of the crosslinking process in complex hydrogel systems. On the other hand, the inhomogeneity of the hydrogel network was demonstrated by low-field nuclear magnetic resonance (LF-NMR) studies. In this way, we obtained information about the crosslink density based on various measurements and were able to further verify the written mathematical model. At the same time, certain deviations of the model from the experimental values were easier to explain. In the field of hydrogel characterization, we focused mainly on the study of nanocellulose, which represents a new period of research in the field of hydrogels. As mentioned earlier, we successfully modified nanocellulose with cationic character, further increasing the number of biopolymers for the development of pH-dependent hydrogels. We also carefully studied the effects of fiber size on the rheological behavior of nanocellulose. Ultimately, it was found that knowledge of the morphological and topographical properties of the hydrogel surface is crucial for the accurate design of hydrogels as delivery systems. The latter is particularly crucial for the mechanisms of adsorption and desorption of drugs on the surface, which was the subject of the last part of the PhD thesis. The third part of the research involves a detailed analysis of the kinetics of adsorption and desorption of proteins on or from the hydrogel surfaces. Lysozyme was used as a model protein. In the last publication presented, the kinetics of adsorption as a function of temperature and ionic strength of the release medium was studied by mathematical modeling of lysozyme release in addition to the already well-developed model for predicting the diffusivity of lysozyme. For the first time, we presented the mechanism for determining the initial (maximum) rate of protein adsorption on the hydrogel surface. At the same time, it was possible to similarly determine the initial (minimum) rate of protein desorption from the surface. The slowing of the adsorption rate and the acceleration of the desorption rate with increasing ionic strength were accurately evaluated mathematically with appropriate parameters. Implementation of the mathematical model for studying adsorption and desorption kinetics into the previously developed model for predicting drug release by the diffusion mechanism allows development of a generalized mathematical model for predicting targeted drug delivery with controlled release as a function of hydrogel design parameters (concentration and type of polymers and crosslinking agents, and understanding of the theory of polymer-polymer interactions during the crosslinking process). 20222022-10-05 09:20:00Doktorsko delo/naloga141693VisID: 12923COBISS_ID: 126021635sl