研究生: |
施博健 Shih, Po-Chien. |
---|---|
論文名稱: |
發展一原位產氫系統用以減緩骨關節炎的發炎 Development of an In Situ H2-Generating System Capable of Alleviating Inflammation in Osteoarthritis |
指導教授: |
宋信文
Sung, Hsin-Wen |
口試委員: |
張燕
Chang, Yen 劉培毅 Liu, Pei-I 賈維焯 Chia, Wei-Cho 黃國政 Huang, Kuo-Cheng |
學位類別: |
碩士 Master |
系所名稱: |
工學院 - 化學工程學系 Department of Chemical Engineering |
論文出版年: | 2017 |
畢業學年度: | 105 |
語文別: | 中文 |
論文頁數: | 35 |
中文關鍵詞: | 骨關節炎 、活性氧化物質 、氫氣緩釋系統 、抗氧化 、抗發炎 |
外文關鍵詞: | osteoarthritis, reactive oxygen species, sustained H2 release system, antioxidant, anti-inflammation |
相關次數: | 點閱:1 下載:0 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
臨床上,過量活性氧化物質(Reactive Oxygen Species, ROS)的產生是促進許多炎症疾病進展的關鍵因素,例如骨關節炎等。氫氣(Hydrogen gas, H2)被視為是一種新的醫學氣體,對細胞和器官具有抗氧化、抗發炎和抗凋亡等保護作用,其最大優點為在體內的施用安全性高且無明顯的副作用。目前給予H2的方式主要有直接吸入含有H2的混合氣體、飲用飽和氫水及透過靜脈或腹腔注射含有H2的生理食鹽水等,而在常溫常壓下H2在水中的溶解度很低且其具有容易逸散的特性,導致這些給予方式在病灶處在短時間內不易有效地累積H2濃度,須長期給予H2。在本研究裡,我們將鎂粉包覆於具疏水性的聚乳酸-甘醇酸(poly lactic-co-glycolic acid, PLGA)載體載體內,以原位注射方式將此微球注射至小鼠的骨關節炎處,藉由發炎處所產生的組織液滲透至微球內部後,與鎂粉進行反應產生H2,除了可以保護因鎂粉造成的組織傷害,也可視為一氫氣緩釋系統,其產氫時間可以延長至3天,且產生的H2可以藉由擴散進入組織和細胞中,於病灶處達到有效的治療濃度,進而清除病灶處所產生的ROS,以達到治療骨關節發炎的效果。
Inflammation is associated with numerous diseases including osteoarthritis, which is featured by the overproduction of reactive oxygen species (ROS). Hydrogen (H2) has been reported to have the capability to reduce oxidative stress by selectively scavenging hydroxyl radical (•OH) with no apparent side effects and can thus be served as a therapeutic medical gas for the treatment of inflammatory diseases. Administration of H2-gas (via inhalation with air), H2-water (via oral intake) or H2-saline (via intravenous drip infusion), has been shown promising in treating several inflammatory diseases in animal models. However, the amount of H2 absorbed by the body systematically through these methods may not enough to scavenge the ROS generated in inflamed tissues, because the solubility of H2 in the biological environment is low. To dissolve this problem, a poly lactic-co-glycolic acid (PLGA) microparticle system containing magnesium powders (Mg@PLGA MPs) that can generate H2 gas in a sustained manner is proposed herein. The feasibility of using the as-prepared Mg@PLGA MPs to scavenge ROS, thus improving local inflammation, is studied in a mouse model with experimentally created osteoarthritis, via local injection.
[1] Lane, N. E., et al. (2011). "OARSI-FDA initiative: defining the disease state of osteoarthritis." Osteoarthritis and Cartilage 19.5: 478-482.
[2] Harvey, W. F., & Hunter, D. J. (2010). "Pharmacologic intervention for osteoarthritis in older adults." Clinics in geriatric medicine 26.3: 503-515.
[3] Chang, K. V., et al. (2013). "Effectiveness of intra-articular hyaluronic acid for ankle osteoarthritis treatment: a systematic review and meta-analysis." Archives of physical medicine and rehabilitation 94.5: 951-960.
[4] Cibulka, M. T., et al. (2009). "Hip Pain and Mobility Deficits—Hip Osteoarthritis: Clinical Practice Guidelines Linked to the International Classification of Functioning, Disability, and Healthfrom the Orthopaedic Section of the American Physical Therapy Association." Journal of Orthopaedic & Sports Physical Therapy 39.4: A1-A25.
[5] Hagen, K. B., et al. (2012). "Exercise therapy for bone and muscle health: an overview of systematic reviews." BMC medicine 10.1: 167.
[6] Rannou, F., et al. (2009). "Splint for base-of-thumb osteoarthritis: a randomized trial." Annals of internal medicine 150.10: 661-669.
[7] Apel, K., & Hirt, H. (2004). "Reactive oxygen species: metabolism, oxidative stress, and signal transduction." Annu. Rev. Plant Biol. 55: 373-399.
[8] Ray, P. D., et al. (2012). "Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling." Cellular signalling 24.5: 981-990.
[9] Lo, Y. Y., & Cruz, T. F. (1995). "Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes." Journal of Biological Chemistry 270.20: 11727-11730.
[10] Hashimoto, S., et al. (1998). "Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis." Arthritis & Rheumatism 41.9: 1632-1638.
[11] Henrotin, Y., Kurz, B., & Aigner, T. (2005). "Oxygen and reactive oxygen species in cartilage degradation: friends or foes?." Osteoarthritis and cartilage 13.8: 643-654.
[12] Lo, Y. Y., et al. (1998). "Interleukin‐1β induction of c‐fos and collagenase expression in articular chondrocytes: Involvement of reactive oxygen species." Journal of cellular biochemistry 69.1: 19-29.
[13] Lepetsos, P., & Papavassiliou, A. G. (2016). "ROS/oxidative stress signaling in osteoarthritis." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1862.4: 576-591.
[14] Ohsawa, I., et al. (2007). "Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals." Nature medicine 13.6: 688-694.
[15] Nakao, A., et al. (2009). "Therapeutic antioxidant medical gas." Journal of clinical biochemistry and nutrition 44.1: 1-13.
[16] Abraini, J. H., et al. (1994). "Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture." Journal of Applied Physiology 76.3: 1113-1118.
[17] Ohsawa, I., et al. (2007). "Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals." Nature medicine 13.6: 688-694..
[18] Fukuda, K. I., et al. (2007). "Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress." Biochemical and biophysical research communications 361.3: 670-674.
[19] Xie, K., et al. (2010). "Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model." Shock 34.5: 495-501.
[20] Itoh, T., et al. (2009). "Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells." Biochemical and biophysical research communications 389.4: 651-656.
[21] Huang, C. S., et al. (2010). "Recent advances in hydrogen research as a therapeutic medical gas." Free radical research 44.9: 971-982.
[22] Hanaoka, T., et al. (2011). "Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide." Medical gas research 1.1: 18.
[23] Kajiyama, S., et al. (2008). "Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance." Nutrition Research 28.3: 137-143.
[24] Cai, J., et al. (2009). "Neuroprotective effects of hydrogen saline in neonatal hypoxia–ischemia rat model." Brain research 1256: 129-137.
[25] De Baaij, J. H., Hoenderop, J. G., & Bindels, R. J. (2015). "Magnesium in man: implications for health and disease." Physiological reviews 95.1: 1-46
[26] Mou, F., et al. (2013). "Self‐Propelled Micromotors Driven by the Magnesium–Water Reaction and Their Hemolytic Properties." Angewandte Chemie International Edition 52.28: 7208-7212.
[27] Mou, F., et al. (2014). "Autonomous motion and temperature-controlled drug delivery of Mg/Pt-Poly (N-isopropylacrylamide) Janus micromotors driven by simulated Body fluid and blood plasma." ACS applied materials & interfaces 6.12: 9897-9903.
[28] Staiger, M. P., et al. (2006). "Magnesium and its alloys as orthopedic biomaterials: a review." Biomaterials 27.9: 1728-1734.
[29] Noviana, D., et al. (2016). "The effect of hydrogen gas evolution of magnesium implant on the postimplantation mortality of rats." Journal of Orthopaedic Translation 5: 9-15.
[30] Tian, P., & Liu, X. (2014). "Surface modification of biodegradable magnesium and its alloys for biomedical applications." Regenerative biomaterials 2.2: 135-151.
[31] Lorenz, C., et al. (2009). "Effect of surface pre-treatments on biocompatibility of magnesium." Acta Biomaterialia 5.7: 2783-2789.
[32] Makadia, H. K., & Siegel, S. J. (2011). "Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier." Polymers 3.3: 1377-1397.
[33] Astete, C. E., & Sabliov, C. M. (2006). "Synthesis and characterization of PLGA nanoparticles." Journal of Biomaterials Science, Polymer Edition 17.3: 247-289.
[34] Ohta, S. (2014). "Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine." Pharmacology & therapeutics 144.1: 1-11.
[35] Agarwal, S., et al. (2016). "Biodegradable magnesium alloys for orthopaedic applications: a review on corrosion, biocompatibility and surface modifications." Materials Science and Engineering: C 68: 948-963.
[36] Pruitt, B. (2010). "Interpreting ABGs: an inside look at your patient's status." Nursing2016 40.7: 31-35.
[37] Sung, H. J., et al. (2004). "The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis." Biomaterials 25.26: 5735-5742.
[38] Hsu, H. Y., & Wen, M. H. (2002). "Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression." Journal of Biological Chemistry 277.25: 22131-22139.
[39] Bulua, A. C., et al. (2011). "Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS)." Journal of Experimental Medicine : jem-20102049.
[40] Poltorak, A., et al. (1998)."Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene." Science 282.5396: 2085-2088.
[41] Lu, Y. C., Yeh, W. C., & Ohashi, P. S. (2008). "LPS/TLR4 signal transduction pathway." Cytokine 42.2: 145-151.
[42] Kelkka, T., et al. (2012). "Enhancement of antibody-induced arthritis via Toll-like receptor 2 stimulation is regulated by granulocyte reactive oxygen species." The American journal of pathology 181.1: 141-150.
[43] Berenbaum, F. (2013). "Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)." Osteoarthritis and Cartilage 21.1: 16-21.
[44] Kapoor, M., et al. (2011). "Role of proinflammatory cytokines in the pathophysiology of osteoarthritis." Nature Reviews Rheumatology 7.1: 33-42.
[45] Jang, E. J., et al. (2015). "Src Tyrosine Kinase Activation by 4-Hydroxynonenal Upregulates p38, ERK/AP-1 Signaling and COX-2 Expression in YPEN-1 Cells." PloS one 10.10: e0129244.
[46] Goldring, M. B., & Otero, M. (2011). "Inflammation in osteoarthritis." Current opinion in rheumatology 23.5: 471.
[47] Sokolove, J., & Lepus, C. M. (2013). "Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations." Therapeutic advances in musculoskeletal disease 5.2: 77-94.