P-tipi uyumlu sıklaştırma yeteneklerine sahip, en küçük kareler spektral eleman metodu tabanlı bir sıkıştırılmayan , laminer akış çözücüsünün geliştirilmesi.

The aim of this thesis is to develop a flow solver that has the ability to obtain an accurate numerical solution fast and efficiently with minimum user intervention. In this study, a two-dimensional viscous, laminar, incompressible flow solver based on Least-Squares Spectral Element Method (LSSEM) is developed. The LSSEM flow solver can work on hp-type nonconforming grids and can perform p-type adaptive refinement. Several benchmark problems are solved in order to validate the solver and successful results are obtained. In particular, it is demonstrated that p-type adaptive refinement on hp-type non-conforming grids can be used to improve the quality of the solution. Moreover, it is found that mass conservation performance of LSSEM can be enhanced by using p-type adaptive refinement strategies while keeping computational costs reasonable.M.S. - Master of Scienc

NANOSCALE FLUID-STRUCTURE INTERACTIONS IN CYTOPLASM DURING FREEZING

In this study, a theoretical model is developed to simulate the biophysical events in the intracellular spaces considering the biphasic, i.e., poroelastic, behavior of the cytoplasm. Most previous studies in the cryobiology literature have modeled the biophysical response of cells to freezing assuming the spatial homogeneity of all physical properties within the intracellular space without considering fluid-structure interaction in both the intracellular and extracellular spaces. However, a few recent studies strongly indicate that spatial heterogeneity in the intracellular space occurs during freezing. We thus model the cytoplasm as a poroelastic material considering nanoscale fluid-structure interaction between the cytoskeleton and cytosol, and the effects of hierarchical fluid-structure interaction across the cell during freezing

Thermal Destabilization of Collagen Matrix Hierarchical Structure by Freeze/Thaw

This study aims to characterize and understand the effects of freezing on collagen structures and functionality. Specifically, thermodynamic destabilization of collagen at molecular- and fibril-levels by combination of low temperatures and freezing were experimentally characterized using modulated differential scanning calorimetry. In order to delineate the effects of sub-zero temperature and water-ice phase change, we hypothesized that the extent of destabilization can be determined based on post-thaw heat induced thermal denaturation of collagen. It is found that thermal denaturation temperature of collagen in hydrogel decreases by 1.4-1.6 degrees C after freeze/thaw while no such decrease is observed in the case of molecular solution. The destabilization is predominantly due to ice formation. Exposure to low temperatures in the absence of ice has only minimal effect. Calorimetry measurements combined with morphological examination of collagen matrices by scanning electron microscopy suggest that freezing results in destabilization of collagen fibrils due to expansion of intrafibrillar space by ice formation. This fibril-level damage can be alleviated by use of cryoprotectant DMSO at concentrations as low as 0.5 M. A theoretical model explaining the change in collagen post-thaw thermal stability by freezing-induced fibril expansion is also proposed

Multifaceted Transport Characteristics of Nanomedicine: Needs for Characterization in Dynamic Environment

Nanomedicine for cancer, where nanoparticles (NPs) are used to deliver drugs, imaging agents, and heat to tumors, shows great potential of improved therapeutic outcomes. In spite of promising early stage results, its clinical efficacy is still significantly limited due to complex transport barriers in vivo. These transport barriers are associated with tumor microenvironment, which is highly complex and heterogeneous and varies spatiotemporally. Thus, in order to improve the in vivo efficacy of nanomedicine, NPs need to be designed and characterized considering their interaction with these complex transport barriers. In this article, thus, we discuss the multifaceted transport characteristics of NPs and their interaction mechanisms with the tumor microenvironment. We also illustrated that NPs have highly spatiotemporal and multiscale distribution around tumor. This dynamic and complex nature of NP transport needs to be taken into consideration in design strategies and evaluation criteria for successful delivery of cancer nanomedicine

EFFECTS OF FREEZING ON COLLAGEN NANOSCALE STRUCTURE IN ENGINEERED TISSUES

The present study aims to systematically investigate the freezing-induced changes that occur at multiple levels of organization of collagen nanostructure in the engineered tissues (ET). Collagen is a major constituent of the extracellular matrix (ECM) of biological tissues, and is also used for scaffold of engineered tissues and biomaterials [1, 2]. Given its abundance and widespread physiological function in vivo, a proper understanding of the relationships between the collagen’s structure, properties, and function is essential for the improvement of current tissue cryopreservation protocols that suffer from highly variable and tissue specific outcomes [3, 4]

In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles

Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. (C) 2017 Wiley Periodicals, Inc

Role of Cells in Freezing-Induced Cell-Fluid-Matrix Interactions Within Engineered Tissues

During cryopreservation, ice forms in the extracellular space resulting in freezing-induced deformation of the tissue, which can be detrimental to the extracellular matrix (ECM) microstructure. Meanwhile, cells dehydrate through an osmotically driven process as the intracellular water is transported to the extracellular space, increasing the volume of fluid for freezing. Therefore, this study examines the effects of cellular presence on tissue deformation and investigates the significance of intracellular water transport and cell-ECM interactions in freezing-induced cell-fluid-matrix interactions. Freezing-induced deformation characteristics were examined through cell image deformetry (CID) measurements of collagenous engineered tissues embedded with different concentrations of MCF7 breast cancer cells versus microspheres as their osmotically inactive counterparts. Additionally, the development of a biophysical model relates the freezing-induced expansion of the tissue due to the cellular water transport and the extracellular freezing thermodynamics for further verification. The magnitude of the freezing-induced dilatation was found to be not affected by the cellular water transport for the cell concentrations considered; however, the deformation patterns for different cell concentrations were different suggesting that cell-matrix interactions may have an effect. It was, therefore, determined that intracellular water transport during freezing was insignificant at the current experimental cell concentrations; however, it may be significant at concentrations similar to native tissue. Finally, the cell-matrix interactions provided mechanical support on the ECM to minimize the expansion regions in the tissues during freezing

Role of intracellular poroelasticity on freezing-induced deformation of cells in engineered tissues

Freezing of biomaterials is important in a wide variety of biomedical applications, including cryopreservation and cryosurgeries. For the success of these applications to various biomaterials, biophysical mechanisms, which determine freezing-induced changes in cells and tissues, need to be well understood. Specifically, the significance of the intracellular mechanics during freezing is not well understood. Thus, we hypothesize that cells interact during freezing with the surroundings such as suspension media and the extracellular matrix (ECM) via two distinct but related mechanisms-water transport and cytoskeletal mechanics. The underlying rationale is that the cytoplasm of the cells has poroelastic nature, which can regulate both cellular water transport and cytoskeletal mechanics. A poroelasticity-based cell dehydration model is developed and confirmed to provide insight into the effects of the hydraulic conductivity and stiffness of the cytoplasm on the dehydration of cells in suspension during freezing. We further investigated the effect of the cytoskeletal structures on the cryoresponse of cells embedded in the ECM by measuring the spatio-temporal intracellular deformation with dermal equivalent as a model tissue. The freezing-induced change in cell, nucleus and cytoplasm volume was quantified, and the possible mechanism of the volumetric change was proposed. The results are discussed considering the hierarchical poroelasticity of biological tissues