Significance of Findings - D I S S E R T A T I O N

The aging society, as well as the increasing number of chronic diseases and resistances to antibiotics, call for treatment options that withstand these challenges. This doctoral thesis comprises valuable data regarding the use of phototherapy for the treatment of wound infections and wound healing. The data confirms that pulsed red LED light improves wound healing not only by photobiomodulatory impact on wound relevant cell types and mechanisms, but in combination with PS also by its efficacy in fighting bacterial infections.

PBM beneficially effects fibroblasts and myoblasts that are stressed by hypoxia/reoxygenation and nutrient-deprived conditions. It was shown that the impact of PBM on the cellular mechanisms under hypoxia is similar, but more pronounced as in a normoxic environment. The increase in oxygen flux, ATP and ROS concentration further confirm the involvement of the electron transport chain, in particular cytochrome c oxidase, in the proposed mechanism of PBM.

The establishment of a simple and close to reality in vivo wound model infected with a naturally occurring polymicrobial suspension, provides the basis for further development of alternative antimicrobial therapeutic approaches. The presented combination of quantitative and qualitative wound analysis allows the use of all kinds of pathogens for wound infection and offers an alternative that is independent of bioluminescence analysis, which became standard in infection wound models.

This is demonstrated by the application of aPDT in this established model. The great potential of the therapy was shown by a significantly improved and faster wound healing of the infected wounds. The discrepancy between the results in vitro and in vivo repeatedly points out the importance of the multi-phase process in clinical trials and the lack of close to reality in vitro wound healing models, which might give an impulse for their faster development.

The gathered information adds important knowledge concerning ischemic and infected wounds and further empowers the development of PBM and aPDT using red LED light.

The optimization of treatment modalities and the identification of additional factors affecting the effects and outcomes, increases the reliability of these alternative therapy approaches and help to reach the best possible therapeutic value for the patients in the future.

Die approbierte gedruckte Originalversion dieser Dissertation ist an der TU Wien Bibliothek verfügbar. The approved original version of this doctoral thesis is available in print at TU Wien Bibliothek.

R

EFERENCES

1. Lindsay M. Biga, S.D., Amy Harwell, Robin Hopkins, Joel Kaufmann, Mike LeMaster, Philip Matern, Katie Morrison-Graham, Devon Quick, and Jon Runyeon, Anatomy &

Physiology. OpenStax/Oregon State University

2. Rodrigues, M., et al., Wound Healing: A Cellular Perspective. Physiol Rev, 2019. 99(1):

p. 665-706.

3. Stefanini, M., Basic mechanisms of hemostasis. Bull N Y Acad Med, 1954. 30(4): p. 239-77.

4. Su, Y. and A. Richmond, Chemokine Regulation of Neutrophil Infiltration of Skin Wounds. Adv Wound Care (New Rochelle), 2015. 4(11): p. 631-640.

5. Brinkmann, V., et al., Neutrophil extracellular traps kill bacteria. Science, 2004.

303(5663): p. 1532-5.

6. Park, J.E. and A. Barbul, Understanding the role of immune regulation in wound healing.

Am J Surg, 2004. 187(5A): p. 11S-16S.

7. Jameson, J., et al., A role for skin gammadelta T cells in wound repair. Science, 2002.

296(5568): p. 747-9.

8. Boismenu, R. and W.L. Havran, Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science, 1994. 266(5188): p. 1253-5.

9. Heath, W.R. and F.R. Carbone, The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol, 2013. 14(10): p. 978-85.

10. Shechter, R. and M. Schwartz, CNS sterile injury: just another wound healing? Trends Mol Med, 2013. 19(3): p. 135-43.

11. Midwood, K.S., L.V. Williams, and J.E. Schwarzbauer, Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol, 2004. 36(6): p. 1031-7.

12. Schultz, G.S., et al., Dynamic reciprocity in the wound microenvironment. Wound Repair Regen, 2011. 19(2): p. 134-48.

13. Greenhalgh, D.G., The role of apoptosis in wound healing. The International Journal of Biochemistry & Cell Biology, 1998. 30(9): p. 1019-1030.

14. Coulombe, P.A., Towards a molecular definition of keratinocyte activation after acute injury to stratified epithelia. Biochem Biophys Res Commun, 1997. 236(2): p. 231-8.

15. Morasso, M.I. and M. Tomic-Canic, Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell, 2005. 97(3): p. 173-83.

16. Pastar, I., et al., Epithelialization in Wound Healing: A Comprehensive Review. Adv Wound Care (New Rochelle), 2014. 3(7): p. 445-464.

17. Gurtner, G.C., et al., Wound repair and regeneration. Nature, 2008. 453(7193): p. 314-21.

18. Levenson, S.M., et al., The Healing of Rat Skin Wounds. Ann Surg, 1965. 161: p. 293-308.

19. Lorenz, H. and M. Longaker, Wounds: Biology, Pathology, and Management. Surgery:

Basic Science and Clinical Evidence: Second Edition, 2008: p. 191-208.

20. Gottrup, F., A specialized wound-healing center concept: importance of a

multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg, 2004. 187(5A): p. 38S-43S.

21. Martin, P. and R. Nunan, Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol, 2015. 173(2): p. 370-8.

22. Kadam, S., et al., Recent Advances in Non-Conventional Antimicrobial Approaches for Chronic Wound Biofilms: Have We Found the 'Chink in the Armor'? Biomedicines, 2019.

7(2).

23. Mustoe, T., Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy. The American Journal of Surgery, 2004. 187(5, Supplement 1): p. S65 - S70.

24. Diegelmann, R.F. and M.C. Evans, Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci, 2004. 9: p. 283-9.

25. MacLeod, A.S. and J.N. Mansbridge, The Innate Immune System in Acute and Chronic Wounds. Adv Wound Care (New Rochelle), 2016. 5(2): p. 65-78.

26. Mustoe, T.A., K. O'Shaughnessy, and O. Kloeters, Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast Reconstr Surg, 2006. 117(7 Suppl): p. 35S-41S.

27. Kingsley, A., The wound infection continuum and its application to clinical practice.

Ostomy Wound Manage, 2003. 49(7A Suppl): p. 1-7.

28. Malone, M., et al., The prevalence of biofilms in chronic wounds: a systematic review and meta-analysis of published data. J Wound Care, 2017. 26(1): p. 20-25.

29. Bowler, P.G., Antibiotic resistance and biofilm tolerance: a combined threat in the treatment of chronic infections. J Wound Care, 2018. 27(5): p. 273-277.

30. Dowd, S.E., et al., Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol, 2008. 8: p. 43.

31. Mastropaolo, M.D., et al., Synergy in polymicrobial infections in a mouse model of type 2 diabetes. Infect Immun, 2005. 73(9): p. 6055-63.

32. Hendricks, K.J., et al., Synergy between Staphylococcus aureus and Pseudomonas aeruginosa in a rat model of complex orthopaedic wounds. J Bone Joint Surg Am, 2001.

83(6): p. 855-61.

33. Founou, R.C., L.L. Founou, and S.Y. Essack, Clinical and economic impact of antibiotic resistance in developing countries: A systematic review and meta-analysis. PLoS One, 2017. 12(12): p. e0189621.

34. Frykberg, R.G. and J. Banks, Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle), 2015. 4(9): p. 560-582.

35. Wollina, U., B. Heinig, and L. Kloth, The Use of Biophysical Technologies in Chronic Wound Management, in Measurements in Wound Healing: Science and Practice, R.

Mani, M. Romanelli, and V. Shukla, Editors. 2013, Springer London: London. p. 313-354.

36. Daniell, M.D. and J.S. Hill, A history of photodynamic therapy. Aust N Z J Surg, 1991.

61(5): p. 340-8.

37. The Nobel Prize in Physiology or Medicine 1903. [cited 2020 January 7th]; Available from: https://www.nobelprize.org/prizes/medicine/1903/summary/.

38. Chung, H., et al., The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng, 2012. 40(2): p. 516-33.

39. Moskvin, S.V., Only lasers can be used for low level laser therapy. Biomedicine (Taipei), 2017. 7(4): p. 22.

40. Hode, L. and J. Tuner, Low-level laser therapy (LLLT) versus light-emitting diode therapy (LEDT): What is the difference? Laser Florence '99. Vol. 4166. 2000: SPIE.

41. Heiskanen, V. and M.R. Hamblin, Photobiomodulation: lasers vs. light emitting diodes?

Photochem Photobiol Sci, 2018. 17(8): p. 1003-1017.

42. Carroll, L. and T.R. Humphreys, LASER-tissue interactions. Clin Dermatol, 2006. 24(1):

p. 2-7.

43. Anderson, R.R. and J.A. Parrish, The optics of human skin. J Invest Dermatol, 1981.

77(1): p. 13-9.

44. Mason, M.G., P. Nicholls, and C.E. Cooper, Re-evaluation of the near infrared spectra of mitochondrial cytochrome c oxidase: Implications for non invasive in vivo monitoring of tissues. Biochim Biophys Acta, 2014. 1837(11): p. 1882-1891.

45. Ferraresi, C., et al., Light-emitting diode therapy in exercise-trained mice increases muscle performance, cytochrome c oxidase activity, ATP and cell proliferation. J Biophotonics, 2015. 8(9): p. 740-54.

46. Karu, T., L. Pyatibrat, and G. Kalendo, Irradiation with He-Ne laser increases ATP level in cells cultivated in vitro. J Photochem Photobiol B, 1995. 27(3): p. 219-23.

47. Benedicenti, S., et al., Intracellular ATP level increases in lymphocytes irradiated with infrared laser light of wavelength 904 nm. Photomed Laser Surg, 2008. 26(5): p. 451-3.

48. Zhang, R., et al., Near infrared light protects cardiomyocytes from hypoxia and

reoxygenation injury by a nitric oxide dependent mechanism. J Mol Cell Cardiol, 2009.

46(1): p. 4-14.

49. Karu, T.I., L.V. Pyatibrat, and N.I. Afanasyeva, Cellular effects of low power laser therapy can be mediated by nitric oxide. Lasers Surg Med, 2005. 36(4): p. 307-14.

50. Lindgard, A., et al., Irradiation at 634 nm releases nitric oxide from human monocytes.

Lasers Med Sci, 2007. 22(1): p. 30-6.

51. Poyton, R.O., K.A. Ball, and P.R. Castello, Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab, 2009. 20(7): p. 332-40.

52. Arany, P.R., et al., Activation of latent TGF-beta1 by low-power laser in vitro correlates with increased TGF-beta1 levels in laser-enhanced oral wound healing. Wound Repair Regen, 2007. 15(6): p. 866-74.

53. Arany, P.R., et al., Photoactivation of endogenous latent transforming growth factor-beta1 directs dental stem cell differentiation for regeneration. Sci Transl Med, 2014.

6(238): p. 238ra69.

54. Faler, B.J., et al., Transforming growth factor-beta and wound healing. Perspect Vasc Surg Endovasc Ther, 2006. 18(1): p. 55-62.

55. Gupta, A., et al., Superpulsed (Ga-As, 904 nm) low-level laser therapy (LLLT) attenuates inflammatory response and enhances healing of burn wounds. J Biophotonics, 2015.

8(6): p. 489-501.

56. Rizzi, C.F., et al., Effects of low-level laser therapy (LLLT) on the nuclear factor (NF)-kappaB signaling pathway in traumatized muscle. Lasers Surg Med, 2006. 38(7): p. 704-13.

57. Hamblin, M.R., Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys, 2017. 4(3): p. 337-361.

58. Lohr, N.L., et al., Enhancement of nitric oxide release from nitrosyl hemoglobin and nitrosyl myoglobin by red/near infrared radiation: potential role in cardioprotection. J Mol Cell Cardiol, 2009. 47(2): p. 256-63.

59. Poyton, R.O. and K.A. Ball, Therapeutic photobiomodulation: nitric oxide and a novel function of mitochondrial cytochrome c oxidase. Discov Med, 2011. 11(57): p. 154-9.

60. Yamasaki, K., et al., Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest, 1998. 101(5): p. 967-71.

61. Bulgrin, J.P., Nitric oxide synthesis is suppressed in steroid-impaired and diabetic wounds. Wounds, 1995. 7: p. 48-57.

62. Wang, Y., et al., Photobiomodulation (blue and green light) encourages osteoblastic-differentiation of human adipose-derived stem cells: role of intracellular calcium and light-gated ion channels. Sci Rep, 2016. 6: p. 33719.

63. Cronin, M.A., M.H. Lieu, and S. Tsunoda, Two stages of light-dependent TRPL-channel translocation in Drosophila photoreceptors. J Cell Sci, 2006. 119(Pt 14): p. 2935-44.

64. Ho, M.W., Illuminating water and life: Emilio Del Giudice. Electromagn Biol Med, 2015.

34(2): p. 113-22.

65. Inoue, S. and M. Kabaya, Biological activities caused by far-infrared radiation. Int J Biometeorol, 1989. 33(3): p. 145-50.

66. Gillette, M.U. and S.A. Tischkau, Suprachiasmatic nucleus: the brain's circadian clock.

Recent Prog Horm Res, 1999. 54: p. 33-58; discussion 58-9.

67. Raab, O., Uber die wirkung Fluorescirender Stoffe auf Infusorien. Z. Biol., 1900. 39: p.

524-546.

68. Jesionek, A. and H. von Tappeiner, Zur Behandlung der Hautcarcinome mit fluoreszierenden Stoffen. Dtsch Arch Klin Med, 1905. 85: p. 223-239.

69. Jodlbauer, A. and H. Von Tappeiner, Die Beteiligung des Sauerstoffs bei der Wirkung fluorescierender Stoffe. Dtsch. Arch. Klin. Med, 1905. 82: p. 520-546.

70. Wainwright, M., Photodynamic antimicrobial chemotherapy (PACT). J Antimicrob Chemother, 1998. 42(1): p. 13-28.

71. Foote, C.S., Definition of type I and type II photosensitized oxidation. Photochem Photobiol, 1991. 54(5): p. 659.

72. Cieplik, F., et al., Antimicrobial photodynamic therapy - what we know and what we don't. Crit Rev Microbiol, 2018. 44(5): p. 571-589.

73. SPILLER, W., et al., Singlet Oxygen Quantum Yields of Different Photosensitizers in Polar Solvents and Micellar Solutions. Journal of Porphyrins and Phthalocyanines, 1998.

02(02): p. 145-158.

74. Baumler, W., et al., Photo-oxidative killing of human colonic cancer cells using indocyanine green and infrared light. Br J Cancer, 1999. 80(3-4): p. 360-3.

75. Halliwell, B. and J.M. Gutteridge, Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet, 1984. 1(8391): p. 1396-7.

76. Meisel, P. and T. Kocher, Photodynamic therapy for periodontal diseases: state of the art. J Photochem Photobiol B, 2005. 79(2): p. 159-70.

77. Alves, E., et al., An insight on bacterial cellular targets of photodynamic inactivation.

Future Med Chem, 2014. 6(2): p. 141-64.

78. Nitzan, Y. and H. Ashkenazi, Photoinactivation of Acinetobacter baumannii and

Escherichia coli B by a cationic hydrophilic porphyrin at various light wavelengths. Curr Microbiol, 2001. 42(6): p. 408-14.

79. Caminos, D.A., et al., Mechanisms of Escherichia coli photodynamic inactivation by an amphiphilic tricationic porphyrin and

5,10,15,20-tetra(4-N,N,N-trimethylammoniumphenyl) porphyrin. Photochem Photobiol Sci, 2008. 7(9): p. 1071-8.

80. Maisch, T., et al., Antibacterial photodynamic therapy in dermatology. Photochem Photobiol Sci, 2004. 3(10): p. 907-17.

81. Vaara, M. and T. Vaara, Polycations sensitize enteric bacteria to antibiotics. Antimicrob Agents Chemother, 1983. 24(1): p. 107-13.

82. Malik, Z., H. Ladan, and Y. Nitzan, Photodynamic inactivation of Gram-negative bacteria:

problems and possible solutions. J Photochem Photobiol B, 1992. 14(3): p. 262-6.

83. Merchat, M., et al., Meso-substituted cationic porphyrins as efficient photosensitizers of gram-positive and gram-negative bacteria. J Photochem Photobiol B, 1996. 32(3): p.

153-7.

84. Minnock, A., et al., Photoinactivation of bacteria. Use of a cationic water-soluble zinc phthalocyanine to photoinactivate both gram-negative and gram-positive bacteria. J Photochem Photobiol B, 1996. 32(3): p. 159-64.

85. Cieplik, F., et al., Antimicrobial photodynamic therapy for inactivation of biofilms formed by oral key pathogens. Front Microbiol, 2014. 5: p. 405.

86. Tim, M., Strategies to optimize photosensitizers for photodynamic inactivation of bacteria. J Photochem Photobiol B, 2015. 150: p. 2-10.

87. Alves, E., et al., Charge effect on the photoinactivation of negative and Gram-positive bacteria by cationic meso-substituted porphyrins. BMC Microbiol, 2009. 9: p. 70.

88. Cieplik, F., et al., Photodynamic biofilm inactivation by SAPYR--an exclusive singlet oxygen photosensitizer. Free Radic Biol Med, 2013. 65: p. 477-487.

89. Soukos, N.S. and J.M. Goodson, Photodynamic therapy in the control of oral biofilms.

Periodontol 2000, 2011. 55(1): p. 143-66.

90. Engel, E., et al., Light-induced decomposition of indocyanine green. Invest Ophthalmol Vis Sci, 2008. 49(5): p. 1777-83.

91. Maisch, T., et al., The role of singlet oxygen and oxygen concentration in photodynamic inactivation of bacteria. Proc Natl Acad Sci U S A, 2007. 104(17): p. 7223-8.

92. Fernandez, J.M.B., M. D.; Grossweiner, L. I., Singlet oxygen generation by

photodynamic agents. Journal of Photochemistry and Photobiology B: Biology, 1997.

37(1): p. 131 - 140.

93. Wilkinson, F., W.P. Helman, and A.B. Ross, Quantum Yields for the Photosensitized Formation of the Lowest Electronically Excited Singlet State of Molecular Oxygen in Solution. Journal of Physical and Chemical Reference Data, 1993. 22(1): p. 113-262.

94. Wilson, B.C. and M.S. Patterson, The physics, biophysics and technology of photodynamic therapy. Phys Med Biol, 2008. 53(9): p. R61-109.

95. Wyatt, T.D., et al., Gentamicin resistant Staphylococcus aureus associated with the use of topical gentamicin. J Antimicrob Chemother, 1977. 3(3): p. 213-7.

96. Wainwright, M., et al., Photoantimicrobials-are we afraid of the light? Lancet Infect Dis, 2017. 17(2): p. e49-e55.

97. Kaye, E.T., Topical antibacterial agents: role in prophylaxis and treatment of bacterial infections. Curr Clin Top Infect Dis, 2000. 20: p. 43-62.

98. Hamblin, M.R., et al., Rapid control of wound infections by targeted photodynamic therapy monitored by in vivo bioluminescence imaging. Photochem Photobiol, 2002.

99. Gad, F., et al., Targeted photodynamic therapy of established soft-tissue infections in mice. Photochem Photobiol Sci, 2004. 3(5): p. 451-8.

100. Komerik, N., et al., Fluorescence biodistribution and photosensitising activity of toluidine blue o on rat buccal mucosa. Lasers Med Sci, 2002. 17(2): p. 86-92.

101. Braham, P., et al., Antimicrobial photodynamic therapy may promote periodontal healing through multiple mechanisms. J Periodontol, 2009. 80(11): p. 1790-8.

102. Brown, S., Clinical antimicrobial photodynamic therapy: phase II studies in chronic wounds. J Natl Compr Canc Netw, 2012. 10 Suppl 2: p. S80-3.

103. Tardivo, J.P., et al., A clinical trial testing the efficacy of PDT in preventing amputation in diabetic patients. Photodiagnosis Photodyn Ther, 2014. 11(3): p. 342-50.

104. Lei, X., et al., A clinical study of photodynamic therapy for chronic skin ulcers in lower limbs infected with Pseudomonas aeruginosa. Arch Dermatol Res, 2015. 307(1): p. 49-55.

105. LibreTexts™, C. EPR - Interpretation. September 30th, 2019 [cited 2020 January 17th];

Available from:

https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook _Maps/Supplemental_Modules_(Physical_and_Theoretical_Chemistry)/Spectroscopy/M

agnetic_Resonance_Spectroscopies/Electron_Paramagnetic_Resonance/EPR_-_Interpretation.

106. Suzen, S., H. Gurer-Orhan, and L. Saso, Detection of Reactive Oxygen and Nitrogen Species by Electron Paramagnetic Resonance (EPR) Technique. Molecules, 2017.

22(1).

107. Dikalov, S.I., Y.F. Polienko, and I. Kirilyuk, Electron Paramagnetic Resonance Measurements of Reactive Oxygen Species by Cyclic Hydroxylamine Spin Probes.

Antioxid Redox Signal, 2018. 28(15): p. 1433-1443.

108. Plesivkova, D., R. Richards, and S. Harbison, A review of the potential of the MinION™

single-molecule sequencing system for forensic applications. WIREs Forensic Science, 2019. 1(1): p. e1323.

109. Rennie, M.Y., et al., Understanding Real-Time Fluorescence Signals from Bacteria and Wound Tissues Observed with the MolecuLight i:X(TM). Diagnostics (Basel), 2019. 9(1).

110. Andreu, N., et al., Optimisation of bioluminescent reporters for use with mycobacteria.

PLoS One, 2010. 5(5): p. e10777.

111. Sen, C.K., et al., Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen, 2009. 17(6): p. 763-71.

112. Zhao, R., et al., Inflammation in Chronic Wounds. Int J Mol Sci, 2016. 17(12).

113. Khan, I. and P. Arany, Biophysical Approaches for Oral Wound Healing: Emphasis on Photobiomodulation. Adv Wound Care (New Rochelle), 2015. 4(12): p. 724-737.

114. Huang, Y.Y., et al., Biphasic dose response in low level light therapy - an update. Dose Response, 2011. 9(4): p. 602-18.

115. Kuliev, R.A. and R.F. Babaev, [Therapeutic action of laser irradiation and

immunomodulators in purulent injuries of the soft tissues in diabetic patients]. Probl Endokrinol (Mosk), 1991. 37(6): p. 31-2.

116. Reddy, G.K., Photobiological basis and clinical role of low-intensity lasers in biology and medicine. J Clin Laser Med Surg, 2004. 22(2): p. 141-50.

117. Zeilinger, K., et al., Effect of energy substrates on the preservation outcome of

hepatocytes and sinusoidal endothelial cells in an experimental hypoxia/reoxygenation model. Transplant Proc, 1997. 29(1-2): p. 403-5.

118. Sugrue, M.E., et al., The use of infrared laser therapy in the treatment of venous ulceration. Ann Vasc Surg, 1990. 4(2): p. 179-81.

119. Byrnes, K.R., et al., Light promotes regeneration and functional recovery and alters the immune response after spinal cord injury. Lasers Surg Med, 2005. 36(3): p. 171-85.

120. Hawkins, D. and H. Abrahamse, Effect of multiple exposures of low-level laser therapy on the cellular responses of wounded human skin fibroblasts. Photomed Laser Surg, 2006. 24(6): p. 705-14.

121. Prabhu, V., et al., Spectroscopic and histological evaluation of wound healing

progression following Low Level Laser Therapy (LLLT). J Biophotonics, 2012. 5(2): p.

168-84.

122. Weiss, N. and U. Oron, Enhancement of muscle regeneration in the rat gastrocnemius muscle by low energy laser irradiation. Anat Embryol (Berl), 1992. 186(5): p. 497-503.

123. Avni, D., et al., Protection of skeletal muscles from ischemic injury: low-level laser therapy increases antioxidant activity. Photomed Laser Surg, 2005. 23(3): p. 273-7.

124. el Sayed, S.O. and M. Dyson, Effect of laser pulse repetition rate and pulse duration on mast cell number and degranulation. Lasers Surg Med, 1996. 19(4): p. 433-7.

125. Karu, T.I. and N.I. Afanas'eva, [Cytochrome c oxidase as the primary photoacceptor upon laser exposure of cultured cells to visible and near IR-range light]. Dokl Akad Nauk, 1995. 342(5): p. 693-5.

126. Moreno, I. and C.C. Sun, Modeling the radiation pattern of LEDs. Opt Express, 2008.

16(3): p. 1808-19.

127. Hashmi, J.T., et al., Effect of pulsing in low-level light therapy. Lasers Surg Med, 2010.

42(6): p. 450-66.

128. Broughton, G., 2nd, J.E. Janis, and C.E. Attinger, The basic science of wound healing.

Plast Reconstr Surg, 2006. 117(7 Suppl): p. 12S-34S.

129. Todd, N.W., I.G. Luzina, and S.P. Atamas, Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair, 2012. 5(1): p. 11.

130. Lev-Tov, H., et al., Inhibition of fibroblast proliferation in vitro using low-level infrared light-emitting diodes. Dermatol Surg, 2013. 39(3 Pt 1): p. 422-5.

131. Mesquita-Ferrari, R.A., et al., No effect of low-level lasers on in vitro myoblast culture.

Indian J Exp Biol, 2011. 49(6): p. 423-8.

132. Rohringer, S., et al., The impact of wavelengths of LED light-therapy on endothelial cells.

Sci Rep, 2017. 7(1): p. 10700.

133. Priglinger, E., et al., Photobiomodulation of freshly isolated human adipose tissue-derived stromal vascular fraction cells by pulsed light-emitting diodes for direct clinical application. J Tissue Eng Regen Med, 2018. 12(6): p. 1352-1362.

134. Munns, S.E. and P.G. Arthur, Stability of oxygen deprivation in glass culture vessels facilitates fast reproducible cell death to cortical neurons under simulated ischemia. Anal Biochem, 2002. 306(1): p. 149-52.

135. Yu, A.C., et al., Changes of ATP and ADP in cultured astrocytes under and after in vitro ischemia. Neurochem Res, 2002. 27(12): p. 1663-8.

136. Topman, G., F.H. Lin, and A. Gefen, The influence of ischemic factors on the migration rates of cell types involved in cutaneous and subcutaneous pressure ulcers. Ann Biomed Eng, 2012. 40(9): p. 1929-39.

137. Santore, M.T., et al., Anoxia-induced apoptosis occurs through a

mitochondria-dependent pathway in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2002.

282(4): p. L727-34.

138. Chen, A.C., et al., Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts. PLoS One, 2011. 6(7): p. e22453.

139. de Freitas, L.F. and M.R. Hamblin, Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy. IEEE J Sel Top Quantum Electron, 2016. 22(3).

140. Yu, W., et al., Photomodulation of oxidative metabolism and electron chain enzymes in rat liver mitochondria. Photochem Photobiol, 1997. 66(6): p. 866-71.

141. Silveira, P.C., et al., Evaluation of mitochondrial respiratory chain activity in muscle healing by low-level laser therapy. J Photochem Photobiol B, 2009. 95(2): p. 89-92.

142. Zungu, I.L., D. Hawkins Evans, and H. Abrahamse, Mitochondrial responses of normal and injured human skin fibroblasts following low level laser irradiation--an in vitro study.

Photochem Photobiol, 2009. 85(4): p. 987-96.

143. Hawkins, D.H. and H. Abrahamse, The role of laser fluence in cell viability, proliferation, and membrane integrity of wounded human skin fibroblasts following helium-neon laser irradiation. Lasers Surg Med, 2006. 38(1): p. 74-83.

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