Browsing by Author "Na, Sungsoo"

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    Application of quantitative analysis in treatment of osteoporosis and osteoarthritis
    (2013-11-08) Chen, Andy Bowei; Yokota, Hiroki, 1955-; Na, Sungsoo; Schild, John H.
    As our population ages, treating bone and joint ailments is becoming increasingly important. Both osteoporosis, a bone disease characterized by a decreased density of mineral in bone, and osteoarthritis, a joint disease characterized by the degeneration of cartilage on the ends of bones, are major causes of decreased movement ability and increased pain. To combat these diseases, many treatments are offered, including drugs and exercise, and much biomedical research is being conducted. However, how can we get the most out of the research we perform and the treatment we do have? One approach is through computational analysis and mathematical modeling. In this thesis, quantitative methods of analysis are applied in different ways to two systems: osteoporosis and osteoarthritis. A mouse model simulating osteoporosis is treated with salubrinal and knee loading. The bone and cell data is used to formulate a system of differential equations to model the response of bone to each treatment. Using Particle Swarm Optimization, optimal treatment regimens are found, including a consideration of budgetary constraints. Additionally, an in vitro model of osteoarthritis in chondrocytes receives RNA silencing of Lrp5. Microarray analysis of gene expression is used to further elucidate the mode of regulation of ADAMTS5, an aggrecanase associated with cartilage degradation, by Lrp5, including the development of a mathematical model. The math model of osteoporosis reveals a quick response to salubrinal and a delayed but substantial response to knee loading. Consideration of cost effectiveness showed that as budgetary constraints increased, treatment did not start until later. The quantitative analysis of ADAMTS5 regulation suggested the involvement of IL1B and p38 MAPK. This research demonstrates the application of quantitative methods to further the usefulness of biomedical and biomolecular research into treatment and signaling pathways. Further work using these techniques can help uncover a bigger picture of osteoarthritis's mode of action and ideal treatment regimens for osteoporosis.
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    Author Correction: Inhibitory effects of dopamine receptor D1 agonist on mammary tumor and bone metastasis
    (Springer Nature, 2022-11-03) Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai‑Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    This corrects the article "Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis" in volume 7, 45686. doi: 10.1038/srep45686
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    Biomechanical and morphological characterization of common iliac vein remodeling: Effects of venous reflux and hypertension
    (2014) Brass, Margaret Mary; Kassab, Ghassan S. (Ghassan Sleewa), 1965-; Na, Sungsoo; Berbari, Edward J.
    The passive properties of the venous wall are important in the development of venous pathology. Increase in venous pressure due to retrograde flow (reflux) and obstruction of venous flow by intrinsic and extrinsic means are the two possible mechanisms for venous hypertension. Reflux is the prevailing theory in the etiology of venous insufficiency. The objective of this thesis is to quantify the passive biomechanical response and structural remodeling of veins subjected to chronic venous reflux and hypertension. To investigate the effects of venous reflux on venous mechanics, the tricuspid valve was injured chronically in canines by disrupting the chordae tendineae. The conventional inflation-extension protocol in conjunction with intravascular ultrasound (IVUS) was utilized to investigate the passive biomechanical response of both control common iliac veins (from 9 dogs) and common iliac veins subjected to chronic venous reflux and hypertension (from 9 dogs). The change in thickness and constituent composition as a result of chronic venous reflux and hypertension was quantified using multiphoton microscopy (MPM) and histological evaluation. Biomechanical results indicate that the veins stiffened and became less compliant when exposed to eight weeks of chronic venous reflux and hypertension. The mechanical stiffening was found to be a result of a significant increase in wall thickness (p < 0.05) and a significant increase in the collagen to elastin ratio (p < 0.05). After eight weeks of chronic reflux, the circumferential Cauchy stress significantly reduced (p < 0.05) due to wall thickening, but was not restored to control levels. This provided a useful model for development and further analysis of chronic venous insufficiency and assessment of possible intervention strategies.
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    Building a Tensegrity-Based Computational Model to Understand Endothelial Alignment Under Flow
    (2021-12) Al-Muhtaseb, Tamara; Ji, Julie; Na, Sungsoo; Tovar, Andres
    Endothelial cells form the lining of the walls of blood vessels and are continuously subjected to mechanical stimuli from the blood flow. Microtubule-organizing center (MTOC), also known as centrosome is a structure found in eukaryotic cells close to the nucleus. MTOC relocates relative to the nucleus when endothelial cells are exposed to shear stress which determines their polarization, thus it plays a critical role in cell migration and wound healing. The nuclear lamina, a mesh-like network that lies underneath the nuclear membrane, is composed of lamins, type V intermediate filament proteins. Mutations in LMNA gene that encodes A-type lamins cause the production of a mutant form of lamin A called progerin and leads to a rare premature aging disease known as Hutchinson-Gilford Progeria Syndrome (HGPS). The goal of this study is to investigate how fluid flow affects the cytoskeleton of endothelial cells. This thesis consists of two main sections; computational mechanical modeling and laboratory experimental work. The mechanical model was implemented using Ansys Workbench software as a tensegrity-based cellular model in order to simulate the state of an endothelial cell under the effects of induced shear stress from the blood fluid flow. This tensegrity-based cellular model - composed of a plasma membrane, cytoplasm, nucleus, microtubules, and actin filaments - aims to understand the effects of the fluid flow on the mechanics of the cytoskeleton. In addition, the laboratory experiments conducted in this study examined the MTOC-nuclear orientation of endothelial cells under shear stress with the presence of wound healing. Wild-type lamin A and progerin-expressing BAECs were studied under static and sheared conditions. Moreover, a custom MATLAB code was utilized to measure the MTOC-nuclear orientation angle and classification. Results demonstrate that shear stress leads to different responses of the MTOC orientation between the wild-type and progerin-expressing cells around the vertical wound edge. Future directions for this study involve additional experimental work together with the improved simulation results to confirm the MTOC orientation relative to the nucleus under shear stress.
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    Coating of Polyvinylchloride for Reduced Cell / Bacterial Adhesion and Antibacterial Properties
    (2019-05) Almousa, Rashed Abdulaziz R.; Xie, Dong; Na, Sungsoo; Li, Jiliang
    A Polyvinylchloride surface was modified by coating a biocompatible, hydrophilic and antibacterial polymer by a mild surface modification method. The surface was first activated and then functionalized, followed by coating with polymer. The surface functionality was evaluated using cell adhesion, bacterial adhesion and bacterial viability for polymers with antibacterial properties. 3T3 mouse fibroblast cells were used for cell adhesion, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus were used for bacterial adhesion in the first study, Pseudomonas aeruginosa and Staphylococcus aureus were used for bacterial adhesion and antibacterial activity in the second study. Chapter 2 reports how we synthesized, immobilized and evaluated a novel hydrophilic polymer with anti-fouling properties onto surface of polyvinylchloride via an effective and mild surface coating technique. The polyvinylchloride surface was first activated by azidation as well as amination, and then tethering a newly synthesized hydrophilic and biocompatible polyvinylpyrrolidone having pendent reactive succinimide functionality onto the surface. Results show that the coated hydrophilic polymer significantly reduced the 3T3 fibroblast cell adhesion as well as the adhesion of the three bacterial species. Chapter 3 reports how we prepared, immobilized and evaluated an antibacterial and anti-fouling polymer onto polyvinylchloride surface following an efficient and simple method of surface modification. The surface coated with a terpolymer constructed with N-vinylpyrrolidone, 3,4-Dichloro-5-hydroxy-2(5H)-furanone derivative and succinimide residue was evaluated with cell adhesion, bacterial adhesion and bacterial viability. Surface adhesion was evaluated with 3T3 mouse fibroblast cells and two bacterial species. Also, antibacterial activity was evaluated by bacterial viability assay with the two bacterial species. Results showed that the polymer-modified polyvinylchloride surface exhibited significantly decreased 3T3 fibroblast cell adhesion and bacterial adhesion. Furthermore, the modified polyvinylchloride surfaces exhibited significant antibacterial functions by inhibiting bacterial growth with bactericidal activity. Altogether, we have successfully modified the surface of polyvinylchloride using a novel efficient and mild surface coating technique. The first hydrophilic polymer-coated polyvinylchloride surface significantly reduced cell adhesion as well as adhesion of three bacterial species. The second hydrophilic and antibacterial polymer-coated polyvinylchloride surface demonstrated significant antibacterial functions by inhibiting bacterial growth and killing bacteria in addition to significantly reduced 3T3 fibroblasts and bacterial adhesions.
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    Developing Novel Antibacterial Dental Filling Composite Restoratives
    (2020-05) Caneli, Gulsah; Xie, Dong; Anderson, Gregory; Na, Sungsoo
    A novel antimicrobial dental composite system has been developed and evaluated. Both alumina and zirconia filler particles were covalently coated with an antibacterial resin and blended into a composite formulation, respectively. Surface hardness and bacterial viability were used to evaluate the coated alumina fi ller-modif ed composite. Compressive strength and bacterial viability were used to evaluate the coated zirconia ller-modi ed composite. Commercial composite Kerr was used as control. The specimens were conditioned in distilled water at 37 °C for 24 h prior to testing. Four bacterial species Streptococcus mutans, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli were used to assess the bacterial viability. Effects of antibacterial moiety content, modif ed particle size and loading, and total fi ller content was investigated. Chapter 2 describes how we studied and evaluated the composite modi fed with antibacterial resin-coated alumina llers. The results showed that almost all the modi ed composites exhibited higher antibacterial activity along with improved surface hardness, as compared to unmodi fed one. Increasing antibacterial moiety content, particle size and loading, and total fi ller content generally increased surface hardness. Increasing antibacterial moiety, fi ller loading, and total fi ller content increased antibacterial activity. On the other hand, increasing particle size showed a negative impact on antibacterial activity. The leaching tests indicate that the modiChapter 3 describes how we studied and evaluated the composite modif ed with antibacterial resin-coated zirconia fi ller. The results showed that almost all the modif ed composites exhibited higher antibacterial activity along with decreased compressive strength, as compared to the unmodif ed control. It was found that with increasing antibacterial moiety content and modi fedfi ller loading, yield strength, modulus and compressive strength of the composite were decreased. In addition, the strengths of the composite were increased with increasing powder/liquid ratio. On the other hand, with increasing antibacterial moiety content, fi ller loading and powder/liquid ratio, antibacterial activity was enhanced. In summary, we have developed a novel antibacterial dental composite system for improved dental restoratives. Both composites modif ed with the antibacterial resin-coated alumina and zirconia fi ller have demonstrated signi cant antibacterial activities. The composite modi fed with the alumina fi ller showed improved hardness values, but the composite modif ed with the zirconia fi ller showed decreased compressive strength values. It appears that the developed system is a non-leaching antibacterial dental composite. ed experimental composite showed no leachable antibacterial component to bacteria.
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    DIFFERENTIAL RHOA ACTIVITY IN CHONDROCYTES UNDER FLOW
    (Office of the Vice Chancellor for Research, 2012-04-13) Wan, Qiaoqiao; Yokota, Hiroki; Na, Sungsoo
    Mechanical force environment is a major factor that influences cellular homeostasis and remodeling. The prevailing wisdom in this field demon-strated that a threshold of mechanical forces or deformation was required to affect cell signaling. However, we hypothesized that RhoA activities can be either elevated or reduced by selecting different levels of shear stress inten-sities. To test this hypothesis, a fluorescence resonance energy transfer (FRET)-based approach was used. The result revealed that C28/I2 chondro-cytes exhibited an increase in RhoA activities in response to high shear stress (10 or 20 dyn/cm2), while they showed a decrease in their RhoA activ-ities to intermediate shear stress at 5 dyn/cm2. No changes were observed under low shear stress (2 dyn/ cm2). The observed two-level switch of RhoA activities was closely linked to the shear stress-induced alterations in actin cytoskeleton and traction forces. In the presence of constitutively active RhoA (RhoA-V14), intermediate shear stress suppressed RhoA activities, while high shear stress failed to activate them. Collectively, these results here suggest that intensities of shear stress are critical in differential activa-tion and inhibition of RhoA activities in chondrocytes.
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    Dose analysis of photobiomodulation therapy on osteoblast, osteoclast, and osteocyte
    (SPIE, 2018-07) Na, Sungsoo; TruongVo, ThucNhi; Jiang, Feifei; Joll, Jeffery E.; Guo, Yunxia; Utreja, Achint; Chen, Jie; Biomedical Engineering, School of Engineering and Technology
    The objective of this study was to evaluate the effects of varying light doses on the viability and cellular activity of osteoblasts, osteocytes, and osteoclasts. A light application device was developed to apply 940-nm wavelength light from light-emitting diodes on three cultured cells, MC3T3-E1, MLO-A5, and RANKL-treated RAW264.7 cells. The doses (energy density) on cells were 0, 1, 5, and 7.5  J  /  cm2. The corresponding light power densities at the cell site were 0, 1.67, 8.33, and 12.5  mW  /  cm2, respectively, and the duration was 10 min. The results showed that the three cell types respond differently to light and their responses were dose dependent. Low-dose treatment (1  J  /  cm2) enhanced osteoblast proliferation, osteoclast differentiation, and osteoclastic bone resorption activity. Osteocyte proliferation was not affected by both low- and high-dose (5  J  /  cm2) treatments. While 1  J  /  cm2 did not affect viability of all three cell types, 5  J  /  cm2 significantly decreased viability of osteocytes and osteoclasts. Osteoblast viability was negatively impacted by the higher dose (7.5  J  /  cm2). The findings suggest that optimal doses exist for osteoblast and osteoclast, which can stimulate cell activities, and there is a safe dose range for each type of cell tested.
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    Effect of Shear Stress on RhoA Activities and Cytoskeletal Organization in Chondrocytes
    (2013-09-05) Wan, Qiaoqiao; Na, Sungsoo; Li, Jiliang; Yokota, Hiroki
    Mechanical force environment is a major factor that influences cellular homeostasis and remodeling. The prevailing wisdom in this field demonstrated that a threshold of mechanical forces or deformation was required to affect cell signaling. However, by using a fluorescence resonance energy transfer (FRET)-based approach, we found that C28/I2 chondrocytes exhibited an increase in RhoA activities in response to high shear stress (10 or 20 dyn/cm2), while they showed a decrease in their RhoA activities to intermediate shear stress at 5 dyn/cm2. No changes were observed under low shear stress (2 dyn/ cm2). The observed two-level switch of RhoA activities was closely linked to the shear stress-induced alterations in actin cytoskeleton and traction forces. In the presence of constitutively active RhoA (RhoA-V14), intermediate shear stress suppressed RhoA activities, while high shear stress failed to activate them. Collectively, these results herein suggest that intensities of shear stress are critical in differential activation and inhibition of RhoA activities in chondrocytes.
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    Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling
    (Spandidos Publications, 2018-09) Wang, Luqi; Wang, Yue; Chen, Andy; Jalali, Aydin; Liu, Shengzhi; Guo, Yunxia; Na, Sungsoo; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Chemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization.