Photobiomodulation Therapy for Age-Related Macular Degeneration and Diabetic Retinopathy: A Review

Figures & data

Table 1 Summary of Available Articles Describing the Application of Photobiomodulation for Age-Related Macular Degeneration. Subjects, Eyes, Wavelength Treated, Device Used, Dose and Delivery Parameters as Well as Results of the Studies are Presented

First Author* (Trial Name, NCT)	Year	Design	Subjects (No.)	Eyes (No.)	λ (nm)	Device	Dose and Delivery Parameters	Results
Begum^Citation24	2013	–	29 CFH knockout mice	39	670	LED Light Source (C.H. Electronics, UK)	20 mW/cm^Citation2 for 720 sec daily for 12 days	Altered morphology of macrophages marked by IBA-1, increased COX expression, 50% reduction of C3 in outer retina, reduced GFAP and vimentin.
Calaza^Citation19	2015	-	44 CFH knockout and 44 C57BL/6 mice	176	670	Unspecified	40 mW/cm^Citation2 for 90 sec daily for 5 days	ATP decline is reversed, but HSP60 (indicator of IR light effect) expression unchanged at 2.4 and 8 month time points.
Kokkinopoulos^Citation26	2013	-	46 C57BL/6 mice	92	670	WARP10 LED Device (Barneveld,WI)	40 mW/cm^Citation2 for 90 sec five times spaced every 35 hours	Shifting C3b from outer retina to RPE-BM interface reduced inflammation (calcitonin, Complement C3d, TNF) and increased mitochondrial polarization.
Rutar^Citation20	2012	-	9 Sprague-Dawley rats	18	670	WARP75 LED Device (Barneveld, WI)	50 mW/cm^Citation2 for 180 sec daily over 5 days	Decreased immunoreactivity (4-hydroxynonenal protein), decreased complement expression C3,C4, reduced C3 deposition in ONL.
Ivandic^Citation40	2008	Prospective trial	203 patients with dry/wet AMD and VA ≤ 20/20	348	780	Custom Device	7.5 mW/cm^Citation2 for two 40 sec treatments over 2 weeks	At 3 and 6 months, both cataract and no-cataract patients had improvement in visual acuity; prevalence of metamorphopsia, scotoma, dyschromatopsia were reduced. In patients with wet AMD, edema and bleeding improved.
Merry^Citation41 (TORPA I)	2012	Prospective Interventional Case Series	9 subjects with dry AMD, 50 or older, VA 20/200-20/20	18	670	WARP10 LED Device (Barneveld,WI)	50–80 mW/cm^Citation2 for eighteen 88 sec treatments over 6 weeks	At 12 months, improved visual acuity by ETDRS chart and contrast sensitivity. No change in fixation stability. Raw data not provided
					790	Gentlewaves (Light bioscience, VA)	6 mW/cm^Citation2 for eighteen 35 sec treatments over 6 weeks
Merry^Citation42 (TORPA 2, NCT02725762)	2017	Prospective Interventional Case Series	24 subjects with AREDS Stages 2–4, ≥ 50 years of age, VA ≥20/200	42	670	WARP10 LED Device (Barneveld, WI)	50–80 mW/cm^Citation2 for nine 88 sec treatments over 2 weeks	At 3 months, 5.14 letter improvement, 0.16 units contrast sensitivity, drusen volume decrease by 0.024 mm^3 and central drusen thickness decreased by mean of 3.78 microns. Stable retinal thickness and retinal volume
					590	Gentlewaves (Light bioscience, VA)	4 mW/cm^Citation2 for nine 35 sec treatments over 2 weeks
					790	Gentlewaves (Light bioscience, VA)	0.6 mW/cm^Citation2 for nine 35 sec treatments over 2 weeks
Markowitz^Citation43 (LIGHTSITE I, NCT02725762)	2019	Randomized, sham controlled, single center study	30 subjects with AREDS Stage 2–4 with VA 20/200-20/40	46	590	Valeda Light Delivery System (Lumithera, WA)	5 mW/cm^Citation2 for nine 250 sec treatments over 4 weeks after baseline; repeated at 24 weeks.	50% of PBT subjects improved by 5 letters (vs 13.6%) at 1 month, improved contrast sensitivity, improved fixation stability, improved quality of life, at 12 months, 70% of study eyes had reduction in drusen volume vs 100% of sham eyes showing increase in drusen volume
					670		65 mW/cm^Citation2 for nine 250 sec treatments over 4 weeks after baseline; repeated at 24 weeks.
					850		8 mW/cm^Citation2 for 250 seconds delivered in 9 treatments over 4 weeks after baseline; repeated at 24 weeks.
LumiThera, Inc.^Citation46 (LIGHTSITE II, NCT03878420)	2019	Double-masked, sham-controlled, parallel design, prospective multi-site study	96 participants ≥ 50 years of age with VA 20/100-20/30 and dry AMD	96	590, 660, 850	Valeda Light Delivery System (Lumithera, WA)	Unspecified	Last update August 2020. Outcomes are BCVA, contrast sensitivity, central drusen volume, central drusen thickness at 9 months
LumiThera, Inc.^Citation47 (LIGHTSITE III, NCT04065490)	2019	Double-masked, sham-controlled, parallel design, prospective multi-site study	96 participants ≥ 50 years of age with VA 20/100-20/32 and dry AMD	96	590, 660, 850	Valeda Light Delivery System (Lumithera, WA)	Unspecified	Last Update February 2020. Outcomes are BCVA, contrast sensitivity, central drusen volume, central drusen thickness at 21 months
LumiThera, Inc.^Citation48 (ELECTROLIGHT, NCT04522999)	2020	Open label, prospective pilot study	15 participants ≥ 50 years of age with VA 20/100-20/32 and dry AMD	15	670	Valeda Light Delivery System (Lumithera, WA)	40 mW/cm^2 for non ? sec treatments over 3 weeks	Last update January 2021. Outcomes are ERG changes on multifocal ERG, photopic negative response, multi-luminance flicker ERG, and fixed-luminance flicker ERG at 3 months and 6 month safer therapy
Grewal^Citation19	2020	Randomized, sham controlled, single center pilot study	42 (12 controls, 30 with intermediate AMD)	42	670	Custom Device	40 mW/cm^2 for 120 sec daily for 52 weeks	Unaltered rod time intercept, no change in scotopic threshold, no change in visual acuity, no change in photopic ERG, no change in ONL, RPE, RPE-BM complexes
Pinelli^Citation44	2020	Case Report	1 patient with dry AMD; unspecified stage	2	590, 660, 850	Valeda Light Delivery System (Lumithera, WA)	Unspecified mW/cm^2 delivered 240 secs daily for 4 weeks	Reduced drusen, improved near/far VA at 1, 3 and 6 months. Subjective vision improvement. Contrast improved from 1.8 to 2.0
Kaymak^Citation45	2020	Case Series	3 patients with intermediate AMD	4	590, 660, 850	Valeda Light Delivery System (Lumithera, WA)	Unspecified mW/cm^2 for ? delivered in 9 sessions over 3 weeks, repeated at 7 months for 4 sessions over 2 weeks	Reduced drusen volume, microperimetry improvements, contrast improvements, subjective improvements in all cases, recordable vision improvement in one case

Notes: *Or responsible party if no single author listed on clincaltrials.gov. ^?Not specified duration of time (N/L) = not listed on clinicaltrials.gov.

Abbreviations: λ, wavelength; CFH, complement factor H; LED, light emitting diode; sec, seconds; ERG, electroretinogram; IBA, ionized calcium binding adaptor molecule 1; COX, cyclooxygenase; GFAP, glial fibrillary acidic protein; ATP, Adenosine Triphosphate; HSP60, heat shock protein 60; RPE-BM, Retinal Pigment Epithelium - Bruch’s Membrane; IR, infrared; AMD, age related macular degeneration; TNF, tumor necrosis factor; ONL, outer nuclear layer; ETDRS, Early Treatment in diabetic Retinopathy Study; AREDS, Age Related Eye Diseases Study; PBT, photobiomodulation therapy; CST, central subfield thickness; VA, visual acuity; ERG, electroretinogram; RPE, retinal pigment epithelium.

Table 2 Summary of Available Articles Describing the Application of Photobiomodulation for Diabetic Retinopathy. Subjects, Eyes, Wavelength Treated, Device Used, Dose and Delivery Parameters as Well as Results of the Studies are Presented

First Author* (Trial Name, NCT)	Year	Design	Subjects (No.)	Eyes (No.)	λ (nm)	Device	Dose and Delivery Parameters	Results
Tang^Citation21	2011	–	20 Lewis rats with diabetes induced by streptozocin	40	670	SpectraLife (Barneveld, WI)	25 mW/cm^2 for 360 sec daily for 16 weeks	Inhibition of the death of retinal ganglion cells, 50% improvement in ERG, superoxide inhibition, increased in antioxidant mnSOD, no significant effect of diabetes on complex IV activity, nitric oxide unchanged
Saliba^Citation23	2015	–	C57BI/6J mice with diabetes induced by streptozocin	120	670	SpectraLife (Barneveld, WI)	20 mW/cm^2 for 240 sec daily for 10 weeks	Inhibition of superoxide, leukostasis, ICAM expression. Change in spatial frequency threshold. No change in nitric oxide. Rescue of the diabetes induced calcium channel dysfunction (a marker of oxidative stress)
Cheng^Citation31	2018	–	C57BI/6J mice with diabetes induced by streptozocin	104–128	670	SpectraLife (Barneveld, WI)	25 mW/cm^2 for 240 s daily for 8 months	Inhibition of the diabetes induced degeneration of retinal capillaries and albumin accumulation in INL and OPL. Preservation of visual function. C-Kit cells and Cyp24a1 are not significant - mechanism might not be mediated by stem cells or VDR signaling
Shen^Citation22 (NIRD, NCT02181400)	2020	Preclinical	Transgenic Müller cell mice	30	670	WARP10 LED Device (Barneveld,WI)	40 mW/cm^2 for 180 sec daily for 9 days	Enhanced photoreceptor mitochondrial membrane, protected Müller cells, protected photoreceptors, reduced retinal vascular leakage
			Sprague Dawley and Dark Agouti Rats		670	Ellex Integre NIR (Minneapolis, MN)	100 or 500 mW/cm^2 for ? sec every two days for 1 week	One week after last treatment, safety assessed. 100 mW/cm^2 safe in pigmented and non-pigmented eyes. 500 mW/cm^2 showed damage in pigmented retina
		Phase II b Clinical Trial	21 adult patients with CI - DME and CST >300 microns	14	670	Ellex Integre NIR (Minneapolis, MN)	25 mW/cm^2 for 90 sec over 12 session for 5 weeks	At 6 months, no significant change in VA. CMT decreased 53±24 microns
				12	670	Ellex Integre NIR (Minneapolis, MN)	100 mW/cm^2 for 90 sec over 12 session for 5 weeks	At 6 months, no significant change in VA. CMT decreased 129±51 microns
				16	670	Ellex Integre NIR (Minneapolis, MN)	200 mW/cm^2 for 90 sec over 12 session for 5 weeks	At 6 months, no significant change in VA. CMT decreased 114±60 microns
Eells^Citation32	2016	Randomized, prospective study	10 individuals with treatment refractory DME	20	670	WARP10 LED Device (Barneveld,WI)	45 mW/cm^2 for ? sec three consecutive days every week for 8 weeks	At 6 months, central retinal thickness declined 24±5 microns (vs 120±97 microns in comparison) and VA improved 6±5 letters (vs 3±4 letter decrease in comparison)
Tang^Citation33	2014	Case Series	2 Patients with non CI-DME, CST > 225 microns and VA > 20/40	4	670	WARP10 LED Device (Barneveld,WI)	56 mW/cm^2 for 120 sec daily for 36 weeks	Thickened areas on spectral domain OCT were reduced by a mean of 20% (±11.7%) in the treated eyes and mean change in the untreated eyes was −3% (±8%)
Bristlecone Health Inc^Citation35 (N/L, NCT03859245)	2019	Interventional	30 patients with DR, AMD, mid-peripheral drusen or DME (Not defined further)	60	660 and 810	Joovv Red LED device (Unspecified)	Unspecified mW/cm^2 for 1200 seconds three times weekly for 36 weeks	Last update March 2019. Combined effect of ketogenic diet and PBT on incidence of hemorrhages, exudates, and macular edema in diabetic retinopathy patient. Impact of the same on size, number and density of drusen.
Kim^Citation36 (N/L, NCT02457975)	2019	Early Phase 1 Clinical Trial	Adult patients with treatment-refractory clinically significant DME	30	670	WARP10 LED Device (Barneveld,WI)	50 mW/cm^2 of light for 90 seconds three consecutive days per week for 8 weeks.	Last update September 2019. Primary outcome measures “VA and OCT changes.”
Glassman^Citation34 (Protocol AE, NCT03866473)	2019	Randomized, masked, Clinical Trial	Adult patients with VA 20/25 or better and CI-DME confirmed by CST >305 microns in men and >290 microns in women	134	670	Retilux Eye Patch (PhotOptx, OH)	25 mW/cm^2 for 180 sec daily (two 90 sec intervals) daily for 16 weeks	Last update March 2021. Primary outcome measures: change in CST on OCT. Secondary outcome measures: Change in retinal volume, alternative treatments for DME, > 5 letter loss in VA, patient compliance

Notes: *Or responsible party if no single author listed on clincaltrials.gov. ^?Not specified duration of time (N/L) = not listed on clinicaltrials.gov.

Abbreviations: λ, wavelength; sec, seconds; ERG, electroretinogram; mnSOD, manganese SuperOxide Dismutase; ICAMs, Intracellular Adhesion Molecules; CMT, Central Macular Thickness; CST, Central Subfield Thickness; VA, visual acuity; LED, light emitting diode; DR, diabetic retinopathy; AMD, age-related macular degeneration; NIR, near infrared laser; OCT, optical coherence tomography; DME, Diabetic Macular Edema; CI-DME, Center-Involving Diabetic Macular Edema.

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