臺灣博碩士論文加值系統

　　細菌性角膜炎乃一嚴重眼部感染疾患。眼表局部施加抗生素藥水乃目前之常規化治療方法。然而，該法除低生物可利用率侷限外，抗生物藥物濫用可能衍生菌種之抗藥性。同時抗生素亦無法抑制細菌性角膜炎所衍生之新生血管病癥。因此，為克服上述瓶頸，本研究擬開發銀奈米材料並採基質注射遞送模式進行細菌性角膜炎治療。本論文製備出棒型、三角形及球型之銀奈米粒子，藉由與細胞、細菌及組織間之交互作用，並將此劃分為兩大主軸進行形狀效應探討。首先，主軸一乃固定奈米粒子重量，結果指出不同形狀粒子之表面積因子影響甚鉅。主軸二乃固定奈米粒子數目，結果建立於不同形狀之細胞內化與結晶度影響因子。最後，通過細菌性角膜炎動物模式之評估，得知球型奈米粒子具有較優異之治療表現，有效地減少組織中菌體之產生、降低後續發炎反應與角膜水腫、遏止組織持續惡化、阻斷併發症之新生血管作用。

　　Bacterial keratitis is a severe eye condition that is caused by pathogen infection. Topical application of antibiotic is currently the common way to treat bacterial keratitis. However, this administration would affect the effectiveness of drug action. In addition, abuse derived from multi-drug resistant strains of the gene and cannot be exempted from the dilemma of corneal neovascularization. Therefore, in order to overcome the above mentioned defect of the current treatment modality, this study intends to develop silver nanomaterials and adopt a intrastromal injection of delivery system for bacterial keratitis treatment. The paper prepared rod, triangular and sphere silver nanoparticles to study the interaction between the cells, bacteria and tissue, and this was divided into two main shaft to explore the shape effect. The first spindle is a fixed weight of nanoparticles, results indicate that the surface area of particles on different shapes factor is importance. The second spindle is fixed the amount of nanoparticles, the results established in the cells of a different shape and degree of crystallinity of influencing factors. Furthermore, we found sphere silver nanoparticles with more outstanding performance of the treatment to effectively reduce the production of bacteria, inflammation, corneal edema, and neovascularization of complications. Our findings suggest that the spherical nanoparticles are the best therapeutic agent among other groups.

目錄
指導教授推薦書
口試委員會審定書
致謝 iii
中文摘要 iv
Abstract v
目錄 vi
圖目錄 xii
第一章 緒論 1
1.1 研究動機 1
1.2 研究目的 2
第二章 文獻回顧 3
2-1. 細菌性角膜炎 3
2-1-1. 病徵 3
2-1-2. 目前治療方針及瓶頸 4
2-2. 銀 5
2-2-1. 銀的運用 6
2-2-2. 致細胞凋亡機理 6
2-2-3. 抗菌機制 7
2-2-4. 影響抗菌能力因子 8
2-2-5. 抗血管新生作用 9
2-3. 奈米技術 9
2-3-1. 特性 10
2-3-2. 製備方式 10
2-3-3. 目前應用 11
第三章 實驗材料與方法 12
3.1 實驗藥品與材料 12
3.2 實驗設備 15
3.3 實驗方法 17
3.3.1 合成銀奈米粒子 17
(1) 棒型奈米粒子 17
(2) 三角形奈米粒子 17
(3) 球型奈米粒子 17
3.3.2 晶格分析 18
3.3.3 光學特性分析 18
3.3.4 細胞相容性 19
(1) 細胞型態分析 20
(2) 細胞活性分析 20
(3) 細胞存活率分析 20
(4) 細胞氧化壓力分析 21
(5) 遺傳物質損傷分析 22
(6) 細胞吞噬量分析 23
3.3.5 抗菌試驗 23
(1) 液態抗菌 23
(2) 固態抗菌 24
3.3.6 抗血管新生檢測 24
(1) 體外抗血管新生試驗 24
(2) 體內抗血管新生試驗 25
3.3.7 臨床觀察 26
(1) 細菌性角膜炎誘發模式 26
(2) 裂隙燈檢查與評分 26
(3) 角膜厚度量測 27
3.3.8 角膜透明度及穿透度分析 27
3.3.9 角膜組織菌體殘留檢測 27
3.3.10 角膜組織材料殘留量 28
3.3.11 組織染色 28
(1) 蘇木紫-伊紅染色 28
(2) 梅生三色染色 28
(3) 革蘭氏染色 29
(4) 免疫染色 29
第四章 結果與討論 31
4.1 型態檢視 31
4.2 晶格分析 33
4.3 光學特性分析 34
第一部分：固定奈米粒子重量 35
4.4 細胞相容性 35
(1) IC25的建立 35
(2) 細胞型態觀察 36
(3) 細胞活性分析 37
(4) 細胞存活率分析 38
(5) 細胞內氧自由基分析 40
(6) 遺傳物質損傷分析 42
(7) 細胞吞噬量分析 44
4.5 抗菌能力 45
4.5.1 MIC90的建立 45
4.5.2 液態抗菌測試 46
4.5.3 固態抗菌測試 47
4.6 抑制血管新生效果 49
4.6.1 體外血管新生 49
4.6.2 體內血管新生 51
第二部分：固定奈米粒子數目 53
4.4 細胞相容性 53
(1) IC25的建立 53
(2) 細胞型態觀察 54
(3) 細胞活性分析 55
(4) 細胞存活率分析 55
(5) 細胞內氧自由基分析 57
(6) 遺傳物質損傷分析 59
(7) 細胞吞噬量分析 60
4.5 抗菌能力 61
4.5.4 MIC90的建立 61
4.5.5 液態抗菌測試 62
4.5.6 固態抗菌測試 63
4.6 抑制血管新生效果 65
4.6.3 體外血管新生 65
4.6.4 體內血管新生 66
第三部分 68
4.7 臨床觀察 68
4.8 角膜透明度及穿透度分析 73
4.9 角膜組織菌體殘留檢測 75
4.10 角膜組織材料殘留量 77
4.11 組織染色 78
(1) 蘇木紫－伊紅染色 78
(2) 梅生三色染色 79
(3) 革蘭氏染色法 81
(4) 免疫染色 82
第五章 結論 83
參考文獻 84

圖目錄
圖1-1 銀奈米粒子用於細菌性角膜炎治療之流程。............................02
圖3-1 銀奈米粒子之實驗流程。 30
圖4-1 R-Ag、T-Ag及S-Ag之型態檢視。................................................31
圖4-2 將製備之銀奈米粒子以X光繞射分析其晶格結構結果圖。....33
圖4-3 利用紫外光-可見光分析銀奈米粒子之表面電漿共振特性。...34
圖4-4 以粒線體功能分析試驗決定銀奈米粒子對兔子角膜基質細胞之抑制25%生長濃度。 35
圖4-5 以光學顯微鏡觀察兔子角膜基質細胞之細胞型態。................36
圖4-6 角膜基質細胞之細胞活性分析。................................................37
圖4-7 角膜基質細胞之細胞毒性檢測。................................................38
圖4-8 角膜基質細胞之氧化壓力測定。................................................40
圖4-9 角膜基質細胞之基因毒性測試。................................................42
圖4-10 兔子角膜基質細胞之吞噬銀奈米粒子之狀態。......................44
圖4-11 銀奈米粒子對金黃色葡萄球菌之抑制90%生長濃度。..........45
圖4-12 以液態培養基觀察金黃色葡萄球菌動態生長曲線。..............46
圖4-13 以固態培養基進行抑制金黃色葡萄球菌能力之評估。..........47
圖4-13 以雞胚絨毛尿囊膜模式進行抑制新生血管之評估。..............49
圖4-14 以動物角膜血管新生模式進行抑制新生血管之評估。..........51
圖4-16 以粒線體功能分析試驗決定銀奈米粒子對兔子角膜基質細胞之抑制25%生長濃度。 53
圖4-17 以光學顯微鏡觀察兔子角膜基質細胞之細胞型態。..............54
圖4-18 角膜基質細胞之細胞活性分析。..............................................55
圖4-19 角膜基質細胞之細胞毒性檢測。..............................................55
圖4-20 角膜基質細胞之氧化壓力測定。..............................................57
圖4-21 角膜基質細胞之基因毒性測試。..............................................59
圖4-22 兔子角膜基質細胞之吞噬銀奈米粒子之狀態。......................60
圖4-23 銀奈米粒子對金黃色葡萄球菌之抑制90%生長濃度。..........61
圖4-24 以液態培養基觀察金黃色葡萄球菌動態生長曲線。..............62
圖4-25 以固態培養基進行抑制金黃色葡萄球菌能力之評估。..........63
圖4-26 以雞胚絨毛尿囊膜模式進行抑制新生血管之評估。..............65
圖4-27 以動物角膜血管新生模式進行抑制新生血管之評估。..........66
圖4-28 於各觀察點進行細菌性角膜炎動物模式之臨床觀察............68
圖4-29 細菌性角膜炎之角膜透明度及穿透度測試。..........................73
圖4-30 以選擇性固態培養基評估銀奈米粒子於動物組織中之抗金黃色葡萄球菌能力。 75
圖4-31 以能量散射光譜觀察銀奈米粒子於動物組織中之殘留情形。 77
圖4-32 以蘇木紫－伊紅染色對動物組織之病理狀態評估。..............78
圖4-33 以梅生三色染色對動物組織之角膜纖維受損狀態評估。......79
圖4-34 以革蘭氏染色對細菌性角膜炎組織之革蘭氏陽性菌之殘留狀態評估。 81
圖4-35 以免疫染色對細菌性角膜炎組織之新生血管狀態評估。......82

1. Dajcs, J.J., et al., The effectiveness of tobramycin and Ocuflox in a prophylaxis model of Staphylococcus keratitis. Curr Eye Res, 2001. 23(1): p. 60-3.
2. Sadrai, Z., et al., Effect of topical azithromycin on corneal innate immune responses. Investigative ophthalmology & visual science, 2011. 52(5): p. 2525-2531.
3. Callegan, M.C., et al., Topical antibiotic therapy for the treatment of experimental Staphylococcus aureus keratitis. Invest Ophthalmol Vis Sci, 1992. 33(11): p. 3017-23.
4. Bodor, N. and P. Buchwald, Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems. AAPS J, 2005. 7(4): p. E820-33.
5. Severin, A., et al., High level oxacillin and vancomycin resistance and altered cell wall composition in Staphylococcus aureus carrying the staphylococcal mecA and the enterococcal vanA gene complex. J Biol Chem, 2004. 279(5): p. 3398-407.
6. Tamber, S., J. Schwartzman, and A.L. Cheung, Role of PknB kinase in antibiotic resistance and virulence in community-acquired methicillin-resistant Staphylococcus aureus strain USA300. Infect Immun, 2010. 78(8): p. 3637-46.
7. Kasetsuwan, N., P. Tanthuvanit, and U. Reinprayoon, The efficacy and safety of 0.5% Levofloxacin versus fortified Cefazolin and Amikacin ophthalmic solution for the treatment of suspected and culture-proven cases of infectious bacterial keratitis: a comparative study. Asian Biomedicine, 2011. 5(1): p. 77-83.
8. Sensoy, D., et al., Bioadhesive sulfacetamide sodium microspheres: evaluation of their effectiveness in the treatment of bacterial keratitis caused by Staphylococcus aureus and Pseudomonas aeruginosa in a rabbit model. Eur J Pharm Biopharm, 2009. 72(3): p. 487-95.
9. Jonsson, P., et al., Virulence of Staphylococcus aureus in a mouse mastitis model: studies of alpha hemolysin, coagulase, and protein A as possible virulence determinants with protoplast fusion and gene cloning. Infect Immun, 1985. 49(3): p. 765-9.
10. Callegan, M.C., et al., Corneal virulence of Staphylococcus aureus: roles of alpha-toxin and protein A in pathogenesis. Infect Immun, 1994. 62(6): p. 2478-82.
11. Lan, W., et al., Nuclear Factor-kappaB: central regulator in ocular surface inflammation and diseases. Ocul Surf, 2012. 10(3): p. 137-48.
12. Schaefer, F., et al., Bacterial keratitis: a prospective clinical and microbiological study. Br J Ophthalmol, 2001. 85(7): p. 842-7.
13. Green, S.N., et al., Protection from Streptococcus pneumoniae keratitis by passive immunization with pneumolysin antiserum. Invest Ophthalmol Vis Sci, 2008. 49(1): p. 290-4.
14. Marquart, M.E. and R.J. O'Callaghan, Infectious Keratitis: Secreted Bacterial Proteins That Mediate Corneal Damage. Journal of Ophthalmology, 2013.
15. Zhang, Z., et al., Plasminogen kringle 5 inhibits alkali-burn-induced corneal neovascularization. Invest Ophthalmol Vis Sci, 2005. 46(11): p. 4062-71.
16. Mochimaru, H., et al., Suppression of alkali burn-induced corneal neovascularization by dendritic cell vaccination targeting VEGF receptor 2. Invest Ophthalmol Vis Sci, 2008. 49(5): p. 2172-7.
17. BenEzra, D., et al., Topical formulations of novel angiostatic steroids inhibit rabbit corneal neovascularization. Invest Ophthalmol Vis Sci, 1997. 38(10): p. 1954-62.
18. Carnahan, M.C. and D.A. Goldstein, Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol, 2000. 11(6): p. 478-83.
19. Rai, M., A. Yadav, and A. Gade, Silver nanoparticles as a new generation of antimicrobials. Biotechnology Advances, 2009. 27(1): p. 76-83.
20. Gong, P., et al., Preparation and antibacterial activity of Fe3O4@Ag nanoparticles. Nanotechnology, 2007. 18(28).
21. Kumar, A., et al., Silver-nanoparticle-embedded antimicrobial paints based on vegetable oil. Nature Materials, 2008. 7(3): p. 236-241.
22. Gurunathan, S., et al., Antiangiogenic properties of silver nanoparticles. Biomaterials, 2009. 30(31): p. 6341-6350.
23. Kalishwaralal, K., et al., Silver nanoparticles inhibit VEGF induced cell proliferation and migration in bovine retinal endothelial cells. Colloids Surf B Biointerfaces, 2009. 73(1): p. 51-7.
24. Grabowska, E., et al., Modification of Titanium(IV) Dioxide with Small Silver Nanoparticles: Application in Photocatalysis. Journal of Physical Chemistry C, 2013. 117(4): p. 1955-1962.
25. Ye, X.M., et al., Fluoro-Jade and silver methods: application to the neuropathology of scrapie, a transmissible spongiform encephalopathy. Brain Research Protocols, 2001. 8(2): p. 104-112.
26. Farajzadeh, M. and A.A. Matin, A new PVC-activated charcoal fiber coated on silver wire; Application in determination of n-alkanes in the headspace of soil samples by SPME-GC. Analytical Sciences, 2002. 18(1): p. 77-81.
27. Madaria, A.R., A. Kumar, and C.W. Zhou, Large scale, highly conductive and patterned transparent films of silver nanowires on arbitrary substrates and their application in touch screens. Nanotechnology, 2011. 22(24).
28. Wang, X.Q., et al., Silver deposits in cutaneous burn scar tissue is a common phenomenon following application of a silver dressing. Journal of Cutaneous Pathology, 2009. 36(7): p. 788-792.
29. Jarrett, F., S. Ellerbe, and R. Demling, Acute leukopenia during topical burn therapy with silver sulfadiazine. Am J Surg, 1978. 135(6): p. 818-9.
30. Yuce, K., et al., Outpatient Management of Bartholin Gland Abscesses and Cysts with Silver-Nitrate. Australian & New Zealand Journal of Obstetrics & Gynaecology, 1994. 34(1): p. 93-96.
31. Brook, I., W.J. Martin, and S.M. Finegold, Effect of silver nitrate application on the conjunctival flora of the newborn: and the occurrence of clostridial conjunctivitis. J Pediatr Ophthalmol Strabismus, 1978. 15(3): p. 179-83.
32. Kim, T.H. and A.Y. Sung, Effects of Ag/Pt nanoparticles on the physical properties of copolymers containing 2-fluoro-5-methylanisole. J Nanosci Nanotechnol, 2013. 13(9): p. 5966-75.
33. Bazzaz, B.S.F., et al., Preparation, characterization and antimicrobial study of a hydrogel (soft contact lens) material impregnated with silver nanoparticles. Contact Lens & Anterior Eye, 2014. 37(3): p. 149-152.
34. Samanta, T., et al., N, N '-Olefin Functionalized Bis-Imidazolium Gold(I) Salt Is an Efficient Candidate to Control Keratitis-Associated Eye Infection. Plos One, 2013. 8(3).
35. Samuel, U. and J.P. Guggenbichler, Prevention of catheter-related infections: the potential of a new nano-silver impregnated catheter. Int J Antimicrob Agents, 2004. 23 Suppl 1: p. S75-8.
36. Chen, J., et al., [Effect of silver nanoparticle dressing on second degree burn wound]. Zhonghua Wai Ke Za Zhi, 2006. 44(1): p. 50-2.
37. Ahlberg, S., et al., Comparison of silver nanoparticles stored under air or argon with respect to the induction of intracellular free radicals and toxic effects toward keratinocytes. Eur J Pharm Biopharm, 2014. 88(3): p. 651-7.
38. AshaRani, P.V., et al., Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano, 2009. 3(2): p. 279-90.
39. Ahamed, M., M.S. Alsalhi, and M.K. Siddiqui, Silver nanoparticle applications and human health. Clin Chim Acta, 2010. 411(23-24): p. 1841-8.
40. McQuillan, J.S., et al., Silver nanoparticle enhanced silver ion stress response in Escherichia coli K12. Nanotoxicology, 2012. 6: p. 857-66.
41. Hernandez, M.E. and D.K. Newman, Extracellular electron transfer. Cellular and Molecular Life Sciences, 2001. 58(11): p. 1562-1571.
42. Hochkoeppler, A., et al., Membrane-associated cytochrome cy of Rhodobacter capsulatus is an electron carrier from the cytochrome bc1 complex to the cytochrome c oxidase during respiration. J Bacteriol, 1995. 177(3): p. 608-13.
43. Morones, J.R., et al., The bactericidal effect of silver nanoparticles. Nanotechnology, 2005. 16(10): p. 2346-53.
44. Loo, S.L., et al., Bactericidal mechanisms revealed for rapid water disinfection by superabsorbent cryogels decorated with silver nanoparticles. Environ Sci Technol, 2015. 49(4): p. 2310-8.
45. Liu, H.L., et al., Antibacterial properties of silver nanoparticles in three different sizes and their nanocomposites with a new waterborne polyurethane. International Journal of Nanomedicine, 2010. 5: p. 1017-1028.
46. Beer, C., et al., Toxicity of silver nanoparticles - nanoparticle or silver ion? Toxicol Lett, 2012. 208(3): p. 286-92.
47. Pal, S., Y.K. Tak, and J.M. Song, Does the antibacterial activity of silver nanoparticles depend on the shape of the nanoparticle? A study of the gram-negative bacterium Escherichia coli. Applied and Environmental Microbiology, 2007. 73(6): p. 1712-1720.
48. Sintubin, L., et al., The antibacterial activity of biogenic silver and its mode of action. Applied Microbiology and Biotechnology, 2011. 91(1): p. 153-162.
49. Kalishwaralal, K., et al., Silver nano - a trove for retinal therapies. J Control Release, 2010. 145(2): p. 76-90.
50. Leonhardt, U., Optical metamaterials - Invisibility cup. Nature Photonics, 2007. 1(4): p. 207-208.
51. Trick of the light. Nature, 2014. 506(7486): p. 6.
52. Lead, J.R. and K.J. Wilkinson, Aquatic colloids and nanoparticles: Current knowledge and future trends. Environmental Chemistry, 2006. 3(3): p. 159-171.
53. Hough, R.M., R.R.P. Noble, and M. Reich, Natural gold nanoparticles. Ore Geology Reviews, 2011. 42(1): p. 55-61.
54. Sousa, E.C., et al., In-field Mossbauer study of disordered surface spins in core/shell ferrite nanoparticles. Journal of Applied Physics, 2009. 106(9).
55. Oates, T.W.H., Real time spectroscopic ellipsometry of nanoparticle growth. Applied Physics Letters, 2006. 88(21).
56. Bell, I.R. and M. Koithan, A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system. Bmc Complementary and Alternative Medicine, 2012. 12.
57. Wang, Y. and N. Herron, Nanometer-Sized Semiconductor Clusters - Materials Synthesis, Quantum Size Effects, and Photophysical Properties. Journal of Physical Chemistry, 1991. 95(2): p. 525-532.
58. Oluwafemi, O.S., et al., A facile completely 'green' size tunable synthesis of maltose-reduced silver nanoparticles without the use of any accelerator. Colloids and Surfaces B-Biointerfaces, 2013. 102: p. 718-723.
59. Ledwith, D.M., A.M. Whelan, and J.M. Kelly, A rapid, straight-forward method for controlling the morphology of stable silver nanoparticles. Journal of Materials Chemistry, 2007. 17(23): p. 2459-2464.
60. Xia, X.H., et al., Quantitative Analysis of the Role Played by Poly(vinylpyrrolidone) in Seed-Mediated Growth of Ag Nanocrystals. Journal of the American Chemical Society, 2012. 134(3): p. 1793-1801.
61. Brown, K.R., D.G. Walter, and M.J. Natan, Seeding of colloidal Au nanoparticle solutions. 2. Improved control of particle size and shape. Chemistry of Materials, 2000. 12(2): p. 306-313.
62. Burns, C., et al., Solution ionic strength effect on gold nanoparticle solution color transition. Talanta, 2006. 69(4): p. 873-876.
63. Nel, A., et al., Toxic potential of materials at the nanolevel. Science, 2006. 311(5761): p. 622-627.
64. Chithrani, B.D., A.A. Ghazani, and W.C.W. Chan, Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Letters, 2006. 6(4): p. 662-668.
65. Heiligtag, F.J. and M. Niederberger, The fascinating world of nanoparticle research. Materials Today, 2013. 16(7-8): p. 262-271.
66. Cai, X., S. Conley, and M. Naash, Nanoparticle applications in ocular gene therapy. Vision Res, 2008. 48(3): p. 319-24.
67. Rana, S., Y.C. Yeh, and V.M. Rotello, Engineering the nanoparticle-protein interface: applications and possibilities. Curr Opin Chem Biol, 2010. 14(6): p. 828-34.
68. Sharma, A., S.V. Madhunapantula, and G.P. Robertson, Toxicological considerations when creating nanoparticle-based drugs and drug delivery systems. Expert Opin Drug Metab Toxicol, 2012. 8(1): p. 47-69.
69. Jia, L.F., et al., Monolayer-Protected Gold Nanoparticle Surface-Bound Catalysts: Preparation and Application. Chinese Journal of Catalysis, 2010. 31(11): p. 1307-1315.
70. Christopher, P. and S. Linic, Shape- and Size-Specific Chemistry of Ag Nanostructures in Catalytic Ethylene Epoxidation. Chemcatchem, 2010. 2(1): p. 78-83.
71. Gratton, S.E.A., et al., The effect of particle design on cellular internalization pathways. Proceedings of the National Academy of Sciences of the United States of America, 2008. 105(33): p. 11613-11618.
72. Cao-Milan, R. and L.M. Liz-Marzan, Gold nanoparticle conjugates: recent advances toward clinical applications. Expert Opinion on Drug Delivery, 2014. 11(5): p. 741-752.
73. Butler, M.R., et al., Topical Silver Nanoparticles Result in Improved Bleb Function by Increasing Filtration and Reducing Fibrosis in a Rabbit Model of Filtration Surgery. Investigative Ophthalmology & Visual Science, 2013. 54(7): p. 4982-4990.
74. Pehlivan, S.B., et al., Preparation and in vitro/in vivo evaluation of cyclosporin A-loaded nanodecorated ocular implants for subconjunctival application. J Pharm Sci, 2015. 104(5): p. 1709-20.
75. Qazi, Y., et al., Nanoparticle-mediated delivery of shRNA.VEGF-a plasmids regresses corneal neovascularization. Invest Ophthalmol Vis Sci, 2012. 53(6): p. 2837-44.
76. Ustundag-Okur, N., et al., Preparation and in vitro-in vivo evaluation of ofloxacin loaded ophthalmic nano structured lipid carriers modified with chitosan oligosaccharide lactate for the treatment of bacterial keratitis. Eur J Pharm Sci, 2014. 63: p. 204-15.
77. Niu, F., et al., Hydrothermal Synthesis of BiFeO3 Nanoparticles for Visible Light Photocatalytic Applications. Journal of Nanoscience and Nanotechnology, 2015. 15(12): p. 9693-9698.
78. Vargas-Lara, F., et al., Intrinsic conductivity of carbon nanotubes and graphene sheets having a realistic geometry. J Chem Phys, 2015. 143(20): p. 204902.
79. Ashkarran, A.A., et al., Bacterial Effects and Protein Corona Evaluations: Crucial Ignored Factors in the Prediction of Bio-Efficacy of Various Forms of Silver Nanoparticles. Chemical Research in Toxicology, 2012. 25(6): p. 1231-1242.
80. Lai, J.Y., Biofunctionalization of gelatin microcarrier with oxidized hyaluronic acid for corneal keratocyte cultivation. Colloids Surf B Biointerfaces, 2014. 122: p. 277-86.
81. Carlson, C., et al., Unique Cellular Interaction of Silver Nanoparticles: Size-Dependent Generation of Reactive Oxygen Species. Journal of Physical Chemistry B, 2008. 112(43): p. 13608-13619.
82. Lai, J.Y. and L.J. Luo, Antioxidant Gallic Acid-Functionalized Biodegradable in Situ Gelling Copolymers for Cytoprotective Antiglaucoma Drug Delivery Systems. Biomacromolecules, 2015. 16(9): p. 2950-63.
83. Collins, A.R., The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol, 2004. 26(3): p. 249-61.
84. Piao, M.J., et al., Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis. Toxicol Lett, 2011. 201(1): p. 92-100.
85. Shrivastava, S., et al., Characterization of enhanced antibacterial effects of novel silver nanoparticles. Nanotechnology, 2007. 18(22).
86. Mondalek, F.G., et al., Inhibition of angiogenesis- and inflammation-inducing factors in human colon cancer cells in vitro and in ovo by free and nanoparticle-encapsulated redox dye, DCPIP. J Nanobiotechnology, 2010. 8: p. 17.
87. Tong, Y.G., et al., Anti-angiogenic effects of Shiraiachrome A, a compound isolated from a Chinese folk medicine used to treat rheumatoid arthritis. European Journal of Pharmacology, 2004. 494(2-3): p. 101-109.
88. Roy, A.M., et al., Antiangiogenic activity of 4 '-thin-beta-D-arabinofuranosylcytosine. Molecular Cancer Therapeutics, 2006. 5(9): p. 2218-2224.
89. Hao, X., et al., Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction. Cardiovasc Res, 2007. 75(1): p. 178-85.
90. Yang, C.F., et al., Experimental corneal neovascularization by basic fibroblast growth factor incorporated into gelatin hydrogel. Ophthalmic Res, 2000. 32(1): p. 19-24.
91. Oksuz, H., et al., Effect of propolis in the treatment of experimental Staphylococcus aureus keratitis in rabbits. Ophthalmic Research, 2005. 37(6): p. 328-334.
92. Callegan, M.C., et al., Topical Antibiotic-Therapy for the Treatment of Experimental Staphylococcus-Aureus Keratitis. Investigative Ophthalmology & Visual Science, 1992. 33(11): p. 3017-3023.
93. Malhotra, A., et al., Ethylene glycol toxicity : MRI brain findings. Clin Neuroradiol, 2016.
94. Carney, E.W., et al., The impact of dose rate on ethylene glycol developmental toxicity and pharmacokinetics in pregnant CD rats. Toxicol Sci, 2011. 119(1): p. 178-88.
95. Orton, D.J., et al., One-step extraction and quantitation of toxic alcohols and ethylene glycol in plasma by capillary gas chromatography (GC) with flame ionization detection (FID). Clin Biochem, 2016. 49(1-2): p. 132-8.
96. Ahlberg, S., et al., PVP-coated, negatively charged silver nanoparticles: A multi-center study of their physicochemical characteristics, cell culture and in vivo experiments. Beilstein J Nanotechnol, 2014. 5: p. 1944-65.
97. Wiley, B., et al., Shape-controlled synthesis of metal nanostructures: The case of silver. Chemistry-a European Journal, 2005. 11(2): p. 454-463.
98. Christopher, P., et al., Shape- and Size-Specific Chemistry of Ag Nanostructures in Catalytic Ethylene Epoxidation. ChemCatChem, 2010. 2(1): p. 78-83.
99. Carrington, L.M. and M. Boulton, Hepatocyte growth factor and keratinocyte growth factor regulation of epithelial and stromal corneal wound healing. J Cataract Refract Surg, 2005. 31(2): p. 412-23.
100. Avalos, A., et al., Cytotoxicity and ROS production of manufactured silver nanoparticles of different sizes in hepatoma and leukemia cells. J Appl Toxicol, 2014. 34(4): p. 413-23.
101. Wang, Z., et al., Silver nanoparticles induced RNA polymerase-silver binding and RNA transcription inhibition in erythroid progenitor cells. ACS Nano, 2013. 7(5): p. 4171-86.
102. Pramanik, S., et al., Unraveling the Interaction of Silver Nanoparticles with Mammalian and Bacterial DNA. J Phys Chem B, 2016. 120(24): p. 5313-24.
103. Das, P., C.D. Metcalfe, and M.A. Xenopoulos, Interactive effects of silver nanoparticles and phosphorus on phytoplankton growth in natural waters. Environ Sci Technol, 2014. 48(8): p. 4573-80.
104. Qiu, L., et al., A cell-targeted, size-photocontrollable, nuclear-uptake nanodrug delivery system for drug-resistant cancer therapy. Nano Lett, 2015. 15(1): p. 457-63.
105. Senapati, V.A., et al., ZnO nanoparticles induced inflammatory response and genotoxicity in human blood cells: A mechanistic approach. Food Chem Toxicol, 2015. 85: p. 61-70.
106. Berthelot-Ricou, A., et al., Genotoxicity assessment of mouse oocytes by comet assay before vitrification and after warming with three vitrification protocols. Fertility and Sterility, 2013. 100(3): p. 882-888.
107. Reidy, B., et al., Mechanisms of Silver Nanoparticle Release, Transformation and Toxicity: A Critical Review of Current Knowledge and Recommendations for Future Studies and Applications. Materials, 2013. 6(6): p. 2295-2350.
108. Gurunathan, S., et al., Antiangiogenic properties of silver nanoparticles. Biomaterials, 2009. 30(31): p. 6341-50.
109. Ge, H., et al., A C-terminal fragment BIGH3 protein with an RGDRGD motif inhibits corneal neovascularization in vitro and in vivo. Exp Eye Res, 2013. 112: p. 10-20.
110. Meyer, N. and C.A. Akdis, Vascular Endothelial Growth Factor as a Key Inducer of Angiogenesis in the Asthmatic Airways. Current Allergy and Asthma Reports, 2013. 13(1): p. 1-9.
111. Vacha, R., F.J. Martinez-Veracoechea, and D. Frenkel, Receptor-Mediated Endocytosis of Nanoparticles of Various Shapes. Nano Letters, 2011. 11(12): p. 5391-5395.
112. Gao, H.J., Probing mechanical principles of cell-nanomaterial interactions. Journal of the Mechanics and Physics of Solids, 2014. 62: p. 312-339.
113. Barua, S., et al., Particle shape enhances specificity of antibody-displaying nanoparticles. Proc Natl Acad Sci U S A, 2013. 110(9): p. 3270-5.
114. Dajcs, J.J., et al., Corneal pathogenesis of Staphylococcus aureus strain Newman. Investigative Ophthalmology & Visual Science, 2002. 43(4): p. 1109-1115.
115. Meyers-Elliott, R.H. and P.A. Chitjian, Immunopathogenesis of corneal inflammation in herpes simplex virus stromal keratitis: role of the polymorphonuclear leukocyte. Invest Ophthalmol Vis Sci, 1981. 20(6): p. 784-98.
116. McClintic, S.M., et al., Visual Outcomes in Treated Bacterial Keratitis: Four Years of Prospective Follow-up. Investigative Ophthalmology & Visual Science, 2014. 55(5): p. 2935-2940.
117. Kim, H.J. and S.W. Oh, Performance Comparison of 5 Selective Media Used to Detect Staphylococcus aureus in Foods. Food Science and Biotechnology, 2010. 19(4): p. 1097-1101.
118. Hume, E.B., et al., Staphylococcus corneal virulence in a new topical model of infection. Invest Ophthalmol Vis Sci, 2001. 42(12): p. 2904-8.
119. Isnard, N., et al., Studies on corneal wound healing. Effect of fucose on iodine vapor-burnt rabbit corneas. Ophthalmologica, 2005. 219(6): p. 324-33.
120. Kowalski, R.P., et al., Intracameral Vigamox (moxifloxacin 0.5%) is non-toxic and effective in preventing endophthalmitis in a rabbit model. Am J Ophthalmol, 2005. 140(3): p. 497-504.
121. Lai, H.J., et al., Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomater, 2014. 10(10): p. 4156-66.
122. Kwan, K.H., et al., Modulation of collagen alignment by silver nanoparticles results in better mechanical properties in wound healing. Nanomedicine, 2011. 7(4): p. 497-504.
123. Mei, L., et al., Bioconjugated nanoparticles for attachment and penetration into pathogenic bacteria. Biomaterials, 2013. 34(38): p. 10328-37.
124. Grigor'eva, A., et al., Fine mechanisms of the interaction of silver nanoparticles with the cells of Salmonella typhimurium and Staphylococcus aureus. Biometals, 2013. 26(3): p. 479-88.
125. Sun, J., et al., Platelet endothelial cell adhesion molecule-1 (PECAM-1) homophilic adhesion is mediated by immunoglobulin-like domains 1 and 2 and depends on the cytoplasmic domain and the level of surface expression. J Biol Chem, 1996. 271(31): p. 18561-70.