The Effects of Blue Light on Human Fibroblasts and Diabetic Wound Healing
Abstract
:1. Introduction
2. Diabetic Wound Healing
3. Wound Healing and Photobiomodulation (PBM)
3.1. The Effect of Red/Near-Infrared (NIR) Light: Mechanisms Involved
3.2. The Effect of Blue Light: Mechanisms Involved
3.3. Antibacterial Effects of Blue Light
3.4. Effects of Blue Light on Fibroblasts and Wound Healing
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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---|---|---|---|
Human fibroblasts (WS1) modelled into wounded, diabetic wounded, and ischemic cell models | Continuous wave diode laser at 660 nm with 5 J/cm2. Control cells received no laser irradiation. Cells were incubated at 37 °C for 30 min post-irradiation. | Upregulation of genes encoding for subunits involved in mitochondrial electron chain complexes I (NADH: ubiquinone Oxidoreductase), IV (cytochrome c oxidase), and V (ATP synthase). | Masha et al. [49] |
Human fibroblasts (WS1) modelled into wounded, diabetic wounded, and ischemic cell models | Mitochondria were isolated from various cell models and irradiated at 660 nm with either 5 or 15 J/cm2. Non-irradiated mitochondria served as controls. | Alteration of mitochondrial function, in particular an increase in cytochrome c oxidase (CCO) activity, as well as an increase in adenosine triphosphate (ATP) synthesis. | Houreld et al. [44] |
HeLa cells | Monochromatic radiation in the range of wavelength 600–860 nm, with a light intensity of 1.3 W/m2, dose 52 J/m2, and irradiation time of 40 s. | Visible red and near-infrared light interacts with photoreceptor molecules like CCO. | Karu et al. [45] |
HeLa cells | Cells were irradiated three times at 632.8 nm, fluence of 6.3 × 103 J/m2 for 10 s. | The redox state of CCO is influenced by visible red light. | Karu et al. [46] |
Sprague Dawley Rat, liver mitochondria | Argon-dye laser at a wavelength of 660 nm, power density of 10 mW/cm, at fluences of 0.6 J/cm2, 1.2 J/cm2, 1.8 J/cm2, 2.4 J/cm2, and 4.8 J/cm2. Experimental fluences were achieved by varying the irradiation times (1, 2, 3, 4, or 8 min). | An increase in enzyme kinetics was found in complex I (NADH ubiquinone oxidoreductase) at fluences of 1.2 J/cm2 and 2.4 J/cm2 and complex III (succinate dehydrogenase) and complex IV (CCO) at fluences of 0.6 J/cm2, 1.2 J/cm2, 2.4 J/cm2, and 4.8 J/cm2. | Yu et al. [48] |
Sprague Dawley Rat, liver mitochondria | Lumination of samples using light emitting diodes (LED) at 629 nm (red), 1 W, 44 lumen; 530 nm (green), 1 W, 30 lumen; 470 nm (blue), 1 W, 10 lumen. Irradiance intensity of 50 mW/cm2. | Mitochondrial respiration inhibited by nitric oxide (NO) and glycerol-trinitrate (GTN) was completely restored by illumination at 430 nm (blue light). | Dungal et al. [55] |
HeLa cells | Blue light (462 nm) irradiation at a fluence of 3.744 J/cm2, frequency of 0.52 mW/cm2, irradiated for 2 h. | Blue light triggers the cytotoxicity of riboflavins in HeLa cells. | Yang et al. [56] |
Human oral mucosa epithelial cells Human skin keratinocytes Bacteria (Pseudomonas aeruginosa) | Blue light (445 nm) at three different protocols: Protocol A: ≤0.30 W/cm2, at 40 J/cm2 (low), 60 J/cm2 (intermediate), and 120 J/cm2 (high); Protocol B: 0.31–0.60 W/cm2, at 40 J/cm2 (low), 60 J/cm2 (intermediate), and 120 J/cm2 (high); Protocol C: ≥0.61 W/cm2, at 40 J/cm2 (low), 60 J/cm2 (intermediate), and 120 J/cm2 (high). | All protocols delivering blue laser light effectively reduced bacterial growth at 24 h. The antimicrobial activity of blue laser light on P. aeruginosa relies on the generation of oxidative stress with minimal toxicity to mammalian cells and tissues. | Rupel et al. [59] |
Human keratinocytes and skin-derived endothelial cells | Light-emitting diodes (LED) irradiation at: 412 nm (0, 33, 66, and 100 J/cm2 at 87 mW/cm2), 419 nm (0, 33, 66, and 100 J/cm2 at 126 mW/cm2), 426 nm (0, 33, 66, and 100 J/cm2 at 68 mW/cm2), 453 nm (0, 33, 66, and 100 J/cm2 at 66 mW/cm2), 632 nm (0, 20, 40, and 60 J/cm2 at 38 mW/cm2), 648 nm (0, 20, 60, and 100 J/cm2 at 71 mW/cm2), 850 nm (0, 60, and 120 J/cm2 at 50 mW/cm2), and 940 nm (0, 40, and 80 J/cm2 at 32 mW/cm2). UVA irradiation, using a mercury arc lamp unit, emitting a UVA spectrum (340–410 nm) with a maximum intensity of 366 nm (84 mW/cm2). | Blue light irradiation with 412–426 nm at high fluences is toxic for endothelial cells and keratinocytes thereby reducing cell numbers. Blue light irradiation with 453 nm is not toxic at high fluences but reduces cell proliferation dose-dependently. Neither red (632–648 nm) nor infrared (850–940 nm) irradiation caused significant changes in cell proliferation. | Liebmann et al. [65] |
3T3 Mouse fibroblasts | Blue light using Quartz–tungsten–halogen (QTH), plasma-arc (PAC), and laser at fluences including 1, 3, 6, 10, 15, 20, 30, and 60 J/cm2. Intensities of 556 mW/cm2 (QTH), 1690 mW/cm2 (PAC), and 202 mW/cm2 (laser) were used. The maximum time for the QTH light source was 120 s (60 J/cm2), based on three 40 s curing cycles. The PAC source was used for up to 30 s (60 J/cm2), and the laser was used for up to 20 s (5 J/cm2). | Suppression of succinic dehydrogenase (SDH) activity of mitochondria ranging from 5 J/cm2 (laser) to 15 J/cm2 (PAC, QTH) up to 72 h post-exposure. Significant suppression of SDH activity at 1 J/cm2 for the PAC source but no suppression was noted for the laser and QTH source. At 3.5 J/cm2, SDH activity suppression was seen in the PAC and QTH sources. Temperature rises ranged from 2 to 9 °C above the base temperature of 37 °C. The cellular effects did not appear to be caused by increases in temperature alone, and the effects were light-dose-dependent. | Wataha et al. [66] |
Human primary retinal epithelial cells | Blue light at 390–550 nm and 2.8 mW/cm2 for 0–9 h. | There was no significant difference in mitochondrial respiration detected at 3 h as compared to controls. However, a small decrease in cell viability was observed at 6 h in irradiated cells. At 9 h cell viability decreased even further. | Godley et al. [67] |
Mouse fibroblasts (NIH 3T3 cells), African green monkey kidney epithelial cells (CV1 cells), and human foreskin keratinocytes (HK cells) | Cells irradiated using a 75 W Xenon Arc Lamp with interference filters at various wavelengths: UVA (375–385 nm), violet (400–410 nm), violet-blue (445–455 nm), blue (450–490 or 485–495 nm), green (495–505 or 500–560 nm), orange (550 long-pass filter), and red (590–650 nm or 605 long-pass filter). | Violet-blue light- and UVA-stimulated hydrogen peroxide production in cultured mouse fibroblast, monkey kidney, and human keratinocytes leading to cellular damage. | Hockberger et al. [68] |
Human skin keratinocytes (HaCaT and hTERT) | Cells were treated with interferon-gamma (INF-γ) and tumour necrosis-alpha (TNF-α) and irradiated with UVB (312 nm at 50 mJ/cm2) and/or blue light (420 nm at 54 mJ/cm2 and 134 mJ/cm2). | Blue light and low-dose UVB treatment of HaCaT and hTERT cells resulted in the inhibition of cytokine-induced production of interleukin (IL)-1α. Exposures to 54 mJ/cm2 and 134 mJ/cm2 showed that blue light had some anti-inflammatory effects. | Shnitkand et al. [69] |
Human keratinocyte (HaCaT), and Human healthy skin samples and fibroblasts | Blue LED (420 nm) at 3.43, 6.87, 13.7, 20.6, 30.9, and 41.2 J/cm2. Power density of 680 mW/cm2 and varying irradiation times from 5 to 60 s. | Blue LED light (410–430 nm) in the range of 3.43–41.2 J/cm2 can modulate metabolism and proliferation in healthy human cells in a dose and cell-dependent manner. | Rossi et al. [70] |
Human gingival fibroblasts | Blue light: Halogen at 750 mW/cm2 and 186 J/cm2 for 240 s. LED 900 mW/cm2 and 162 J/cm2 for 180 s. Plasma arc irradiation 2000 mW/cm2 and 240 J/cm2 for 120 s. | All types of blue light irradiation have led to diminished cell proliferation by 40% one-week post exposure and were not attributed to the formation of DNA double-strand breaks and cannot be annulled by N-acetyl-cysteine. | Taoufik et al. [72] |
Human dermal fibroblasts (HDF) | Blue LED light at 410, 420, 453, 480 nm with 0 J/cm2, 15 J/cm2, 30 J/cm2, 60 J/cm2, 90 J/cm2. Power density of 50 mW/cm2. | Blue LED light causes toxicity and reduced proliferation in human dermal fibroblasts in a dose and wavelength-dependent manner. Toxicity was identified at 410 nm (60 J/cm2) and 420 nm (60 J/cm2 and 90 J/cm2). There was an increase in intracellular oxidative stress in a wavelength-dependent manner (410 nm and 420 nm). Blue LED light also led to an increase in the sensitivity of human dermal fibroblasts to hydrogen peroxide. | Opländer et al. [73] |
Human skin fibroblasts | LED-generated blue light (LED-BL) with 415 ± 15 nm at 350 W/m2 (0, 5, 10, 15, 30, 45, and 80 J/cm2). | LED-BL (415 nm) inhibits fibroblast proliferation in a dose-dependent manner without causing significant effects on viability at fluences of 10, 15, 30, or 80 J/cm2. Irradiation with fluences of 5, 30, 45, and 80 J/cm2 decreased fibroblast migration speed, and fluences of 5, 10, 30, and 80 J/cm2 resulted in an increase in reactive oxygen species. | Mamalis et al. [74] |
Human skin fibroblasts | Blue light at 470 nm (30 mW/cm2). Cells were irradiated with a fluence of 3, 55, 110, and 220 J/cm2 and incubated for 24 h. | It was found that the MTT and Trypan Blue assay identified a significant decrease in cell viability when irradiated with 55, 110, and 220 J/cm2. At 3, 55, 110, and 220 J/cm2 the live/dead fluorescence assay identified only a slight decrease in cell viability. The neutral red assay identified a significant decrease in cell viability with 220 J/cm. Irradiation with 3 J/cm2 or 55 J/cm2 did not adversely affect cell viability. Thus, doses below 110 J/cm2 appear safe. As the dose increased, there appeared to be an alteration in mitochondrial metabolism, followed by lysosomal dysfunction, membrane disruption, and the eventual loss of cell membrane integrity. | Masson-Meyers et al. [75] |
Mouse aortas | Irradiation doses were delivered via cold light lamp (Opelco 20500/06) (40,000–190,000 lux), light diodes [red (620–750 nm), green (495–570 nm), or blue (380–495 nm)] or a monochromator with varying wavelengths. | OPN4 mediates photorelaxation in blood vessels. Vasorelaxation is wavelength-specific, with a maximal response at ~430–460 nm. | Sikka et al. [81] |
Human Keratinocytes Additionally, human hair follicles | LED-based device, hair follicles were irradiated with 453 or 689 nm wavelengths, 16 mW/cm2 irradiance (3.2 J/cm2) radiant exposures during 10 consecutive days. Cell monolayers were treated with 3.2 J/cm2 light (453 nm) | The expression of OPN2 and OPN3 was detected in skin and hair follicles. Treatment with 3.2 J/cm2 of blue light with 453 nm was seen to sustain cell proliferation of the outer root sheath cells and thereby have a positive on hair growth ex vivo. | Buscone et al. [82] |
Human keratinocytes and dermal fibroblasts Human ex vivo: epithelial tongue cells | LED-based devices at 447, 505, 530, 655, and 850 nm wavelengths in vitro. Ex vivo wounds were irradiated daily with two proprietary LED devices emitting 453 nm light at 2 J/cm2 or 656 nm at 30 J/cm2 | Blue light stimulated wound closure, with a corresponding increase in OPN3 expression. Blue light had no effect on keratinocyte morphology and migration (scratch-wound assay) but did cause a decrease in DNA synthesis, and at a higher fluence of 30 J/cm2, migration was inhibited. | Castellano-Pellicena [83] |
Bacteria (methicillin-resistant Staphylococcus aureus; MRSA) | Violet/blue visible diode laser (405 nm), fluence of 121 J/cm2, power density of 135 mW/cm2, irradiated for 15 min. One or two irradiations. | Blue light rapidly suppresses MRSA by the alteration of membrane integrity with a decrease in membrane polarisation and alteration of vital cellular functions. MRSA activity is suppressed 5 min after the first dose and continues after the second dose. Two doses of blue light administered 30 min apart are more effective in reducing the number of viable cells than a single dose. | Biener et al. [61] |
Bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) | A single blue laser irradiation (450 nm) at fluences of 0 (control), 3, 6, 12, 18, and 24 J/cm2. | S. aureus and P. aeruginosa inhibition at low fluences (>6 J/cm2), maintained for up to 48 h post irradiation, with no dose-dependent relationships noted. E. coli was inhibited at all fluences except at 24 J/cm2. | De Sousa et al. [62] |
Bacteria (Cutibacterium acnes) | Bacteria irradiated three times per day at 3 or 4 h intervals over three or more days using a pulsed laser (450 nm) with fluencies of 3 or 5 J/cm2 and irradiance at 2 mW/cm2. C. acnes fluorescence intensity was measured at decreasing radiant exposures of 5, 3.6, and 3 J/cm2 on days one, two and three; and then 5 and 3.6 J/cm2 on day four at 2 mW/cm2. | Total (100%) bacterial suppression is achievable using 5 J/cm2 when applied three times per day at 3 h intervals over a three-day period. C. acnes fluoresce predominantly in the red wavelength range and diminish progressively with repeated irradiation at 3 h intervals; however, a resurgence of bacterial growth after long periods of no treatment was noted. | Bumah et al. [63] |
Bacteria (Cutibacterium acnes and methicillin-resistant Staphylococcus aureus) in planktonic cultures, forming biofilms or formed biofilms | Planktonic bacteria cultures: MRSA irradiated at 450 nm (3 mW/cm2), with 0, 4.5, 5.4, or 7.6 J/cm2 three times at 30 min intervals; C. acnes cultures irradiated with 2 mW/cm2, 0, 3.6 or 5 J/cm2 thrice daily for three days at 3 h intervals. Forming biofilms irradiated at 450 nm (2 mW/cm2) with 0 or 7.6 J/cm2 three times per day for three days. MRSA irradiated at 30 min intervals and P. acnes irradiated at 3 h intervals. Established biofilms of MRSA and C. acnes were irradiated with pulsed light at 450 nm (2 mW/cm2) three times a day for 3 days either at 7.6 J/cm2 or 10.8 J/cm2. | Total (100%) bacterial suppression in planktonic cultures of MRSA and C. acnes with 7.6 J/cm2 and 5 J/cm2, respectively. There was no significant decrease in both bacteria in terms of the rate of biofilm formation, and the antimicrobial effects in forming and formed biofilms were minimal. However, increasing the radiant exposure to 10.8 J/cm2 yielded more disruption of the biofilm and fewer live MRSA and C. acnes were noted. | Bumah et al. [64] |
Sprague Dawley Rat, infected excision wound | Blue Light (445 nm), at ≤0.30 W/cm2 and 60 J/cm2. Irradiation was performed at 30 min or at 24 h after infection with P. aeruginosa. | The inhibition of the progression of wound superinfection through intracellular ROS production. | Rupel et al. [59] |
Sprague Dawley Rat, excision wound | Group 1 was treated with blue LED (470 nm, 1 W), Group 2 was treated with red LED (629 nm, 1 W), and Group 3 was not illuminated (control). For each light source, irradiance was 50 mW/cm2, and irradiation took place post-operatively and on five consecutive days for 10 min. | Blue light significantly reduced wound size by 50% on day 7 post-operatively. There appeared to be enhanced epithelisation. Both wavelengths also affected keratin mRNA expression. | Adamskaya et al. [71] |
Hairless mice expressing roGFP1 Human live skin Human keratinocyte cells (HaCaT) | Mice irradiated with high-power LED-emitting UVA (365 nm), blue (460 nm), green (523 nm), red (623 nm), far red (740 nm), or infrared (850 nm). Mouse autofluorescence was recorded every 10 s. After 5 min of baseline recording, the skin was exposed to the LED light for 5 s (duty cycle 50%) between each fluorescence recording. HaCaT cells were irradiated with UVA (365 nm), blue (460 nm), and green (523 nm) light LED. Fluorescence ratios were recorded every 15 s, and cells were exposed to LED light for 7.5 s in between ratio recordings (duty cycle 50%). Human skin (left and right hands) irradiated with blue light equivalent to the blue component of direct sunlight. The average irradiance was 11 mW cm2 and corresponds to the high energy blue light component (wavelengths 400–480 nm). Human skin autofluorescence was recorded every 10 s. After 5 min baseline, blue light illumination was initiated at 80% duty cycle (8 s of illumination at 460 nm and 13.8 mW cm2 every 10 s) for 10 min, followed by another 5 min of autofluorescence recording without blue light illumination. | Blue light could produce oxidative stress in live skin, preferentially in mitochondria, but green, red, far red, or infrared light did not. Blue light-induced oxidative stress was also detected in cultured human keratinocytes. Skin autofluorescence was reduced by blue light, suggesting flavins are the photosensitiser. Exposing human skin to the blue light contained in sunlight depressed flavin autofluorescence, demonstrating that the visible component of sunlight has a physiologically significant effect on human skin. Blue light contributes to skin ageing similar to UVA. | Nakashima et al. [76] |
Human live skin | Photodynamic therapy (PDT) lamp with an emission spectrum between 380 and 480 nm and peak emission at 420 nm. Irradiation was given on five consecutive days with 20 J/cm2, with a cumulative dose of 100 J/cm2. | No inflammatory cells and sunburn cells were visible before or after irradiation. However, there was an increase in the perinuclear vacuolisation of keratinocytes after 48 h. Irradiation does not cause DNA damage or early photo-ageing. Minimal hyperpigmentation of the irradiated skin was seen. | Kleinpenning et al. [77] |
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Purbhoo-Makan, M.; Houreld, N.N.; Enwemeka, C.S. The Effects of Blue Light on Human Fibroblasts and Diabetic Wound Healing. Life 2022, 12, 1431. https://doi.org/10.3390/life12091431
Purbhoo-Makan M, Houreld NN, Enwemeka CS. The Effects of Blue Light on Human Fibroblasts and Diabetic Wound Healing. Life. 2022; 12(9):1431. https://doi.org/10.3390/life12091431
Chicago/Turabian StylePurbhoo-Makan, Meesha, Nicolette Nadene Houreld, and Chukuka S. Enwemeka. 2022. "The Effects of Blue Light on Human Fibroblasts and Diabetic Wound Healing" Life 12, no. 9: 1431. https://doi.org/10.3390/life12091431