Peripheral retinal irradiation with low-energy red light can effectively and safely delay the progression of myopia

Abstract

Aims

To determine whether peripheral retinal irradiation with low-energy red light can effectively and safely delay the progression of myopia.

Methods

The guinea pigs (age, 2 weeks) were used. The central or peripheral retina was exposed to red light for 3 min each at 9:00 AM and 5:00 PM daily. At day 28, examinations were performed to assess the condition of axial length, the cornea and lens, and the central choroid thickness. The ratio of axial length at a given time to the baseline axial length was used to assess the axial length growth.

Results

Under the same energy density mode, illuminance (energy density) on the retina layer of peripheral irradiation is less than that of central irradiation. Under myopia induction, after 4 weeks of red light irradiation, the axial length ratios of the central and peripheral irradiation groups were 1.09±0.02 and 1.07±0.02, respectively, both significantly lower than the axial length ratio of 1.11±0.01 in the group with only myopia induction. Peripheral irradiation outperformed central irradiation in delaying axial elongation (p<0.05). Under the premise of myopia induction, peripheral irradiation but not central irradiation at 0.6 mW/cm² still delayed axial elongation. Both central and peripheral irradiation increased central choroidal thickness, with peripheral irradiation having a more pronounced effect.

Conclusion

Peripheral retinal irradiation with low-energy red light can effectively and safely slow axial growth while increasing central choroidal thickness. The follow-up period for the current study is 28 days, and the long-term safety of red light therapy for myopia necessitates further investigation.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Central retinal irradiation with low-energy light is effective in myopia control, with a potential macular photo-damage.

WHAT THIS STUDY ADDS

• We revealed that peripheral retinal irradiation with low-energy red light may be more effective than central irradiation for myopia prevention and control (p<0.05).

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Peripheral retinal red light irradiation is more effective than central retinal red light irradiation, which makes it possible to use a much lower-energy red light to delay the development of myopia.

Introduction

In recent years, repeated low-energy red light irradiation of the retina to delay the progression of myopia has been substantiated by many studies,¹,³ with its therapeutic efficacy being encouraging. Literature even suggests that its effectiveness is not inferior to orthokeratology,⁴ positing it as one of the most effective current measures for myopia prevention and control. Some patients have even exhibited axis length reductions following red light therapy.^{5 6} Due to its significant efficacy, the National Health Commission of China endorsed clinical trials of red light therapy in an official document in July 2022.⁷ However, red light therapy for myopia has also been met with opposition from some ophthalmologists, primarily concerning its safety. Since current red light therapy mainly targets the macular region, which is known for its sensitivity and vulnerability to light irradiation, any pathological changes here can severely affect vision. Considering the mechanism of red light therapy for myopia is not fully elucidated, the impact of repeated irradiation on the macular region remains unclear. Although short-term safety appears high, there have been cases of maculopathy post-irradiation,⁸ and the long-term risks are not yet confirmed.

Compared with the small area of the macular retina, there is a larger area of non-macular region, which has a far lesser impact on vision. Could irradiation of the peripheral non-macular region achieve the same myopia control effects as macular irradiation? If so, we could significantly reduce the risk while maintaining efficacy, as even potential photodamage in non-macular areas would pose less risk than macular damage. This study compares the effects of central and peripheral retinal red light irradiation on myopia prevention and control.

Materials and methods

Two-week-old tricolour Guinea pigs were purchased from the Jinan Jinfeng Animal Centre (Jinan, China). The animals were housed in standard cages in a light-controlled room at a temperature of 23°C±2°C and a 12-hour light-dark cycle (8AM to 8PM). The animals were given food and water ad libitum. This study was approved by the Animal Care and Ethics Committee of Shandong First Medical University, Jinan, China (approval number: LS2024009). The care and treatment of animals complied with the Association for Research in Vision and Ophthalmology Statement on the Use of Animals in Ophthalmic and Vision Research. A total of 48 eyes in 24 animals were randomly and evenly divided into six groups: blank control, central red light irradiation, peripheral red light irradiation, lens induced myopia (LIM), LIM with central red light irradiation and LIM with peripheral red light irradiation. SPSS (Version 21, USA) software was used to generate the randomisation sequence. The blank and LIM groups served as control groups for us to obtain data on axial length growth under normal conditions and myopia-induced conditions, respectively. This allows us to evaluate the myopia-delaying effects of red light irradiation under both normal and myopia-induced states. Myopia model in the LIM group was established with −4D lenses as described in the previous study.^{9 10} Sample size was determined by the researchers and animal availability. No animal was excluded during the experiment due to eye inflammation or other eye diseases.

A red light irradiation device (Sunvisionmed Technology Co., Ltd, China) was used for central and peripheral red light irradiation. The device contains a 32 cm diameter circular red light emitter with a wavelength of 650 nm and irradiation distance of 3.12 cm. Light energy density is adjustable. For central irradiation, a 2 cm diameter central area was exposed, while peripheral areas were covered (figure 1A) and vice versa for peripheral irradiation (figure 1B).

Figure 1. For central irradiation, a 2 cm diameter central area was exposed, while peripheral areas were covered (A), and vice versa for peripheral irradiation (B). Under central irradiation, a single circular red spot appeared on the semi-transparent membrane (C), while peripheral irradiation resulted in a ring-shaped red spot with no central red light (D).

The default setting delivered red light with an energy density of 1.8 mW/cm² at pupil layer under both central and peripheral irradiation model. Red light irradiation was conducted for 3 min each at 9 AM and 5 PM daily. Axial length was measured using A-scan ultrasonography (KAIXIN OD1-A, Xuzhou, China) at baseline and on day 3, 7, 14, 21 and 28. Two experienced optometrists conducted the measurements, and on establishing consistent readings in a preliminary test, mean values from both were used. The ratio of axial length at a given time to the baseline axial length was used to assess the axial length growth. At day 28, animals were euthanised with an overdose of peritoneal injection of pentobarbital. Eyes were enucleated, and histopathological staining was performed. Haematoxylin and eosin (H&E), TUJ-1 immunohistochemistry and TUNEL assays were used to assess morphological changes in retinal ganglion cells and associated ocular tissues. Slit-lamp biomicroscopy confirmed corneal and lens status.

Optical coherence tomography (DREAM OCT-Intalight, China) assessed central choroidal thickness (CCT). Following anaesthesia of the animals, the retina cross line scanning mode was employed, which includes two perpendicularly aligned 9 mm lines, each with 1024 A-scans. Choroidal thickness measurements were taken from the outer boundary of the hyper-reflective retinal pigment epithelium (RPE) line to the hyper-reflective inner scleral border (figure 2). The CT of 18 radial lines that were 3 mm from the optic disc was measured manually. CCT is the average value of the above data. The ratio of CCT at a given time to the baseline axial length was used to assess the changes of CCT.

Figure 2. Choroidal thickness (CT) measurements were taken from the outer boundary of the hyper-reflective retinal pigment epithelium (RPE) line to the hyper-reflective inner scleral border (Figure 2).

The investigators were blinded to group allocation during data collection or analysis. Data was presented as mean±SD when needed. SPSS (Version 21, USA) software was used for data analysis.

Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.

Results

Illumination mode assessment

A circular dark box with a thickness of 7 mm, with a 3 mm diameter hole on one side and a milky semi-transparent membrane on the other was used to simulate an eyeball. Under central irradiation, a single circular red spot appeared on the semi-transparent membrane (figure 1C), while peripheral irradiation resulted in a ring-shaped red spot with no central red light (figure 1D). The luminous area of central irradiation is much smaller than that of peripheral irradiation. Under the same energy density mode, the illuminance (energy density) of red light projected on the membrane by peripheral irradiation is less than that of central irradiation.

Comparison of the effectiveness of central and peripheral red light irradiation

The baseline axial length of group blank control, central red light irradiation, peripheral red light irradiation, LIM, LIM with central red light irradiation and LIM with peripheral red light irradiation was 6.76±0.06 mm, 6.92±0.09 mm, 6.88±0.04 mm, 6.94±0.11 mm, 6.98±0.04 mm 6.94±0.16 mm. No significance was observed among the baseline axial lengths of different groups.

Without inducing myopia, the axial length ratios of the central (n=8) and peripheral (n=8) irradiation groups after 4 weeks of red light exposure were 1.06±0.01 and 1.05±0.01, respectively, both significantly lower than the axial length ratio of 1.08±0.01 in the blank control group (n=8). Under myopia induction, after 4 weeks of red light irradiation, the axial length ratios of the central (n=8) and peripheral (n=8) irradiation groups were 1.09±0.02 and 1.07±0.02, respectively, both significantly lower than the axial length ratio of 1.11±0.01 in the group with only myopia induction (n=8). Peripheral irradiation consistently outperformed central irradiation in delaying axial elongation regardless of myopia induction status (figure 3) (p<0.05).

Figure 3. Without inducing myopia, the axial length ratios of the central (n=8) and peripheral (n=8) irradiation groups after 4 weeks of red light exposure were 1.06±0.01 and 1.05±0.01, respectively, both significantly lower than the axial length ratio of 1.08±0.01 in the blank control group (n=8). Under myopia induction, after 4 weeks of red light irradiation, the axial length ratios of the central (n=8) and peripheral (n=8) irradiation groups were 1.09±0.02 and 1.07±0.02, respectively, both significantly lower than the axial length ratio of 1.11±0.01 in the group with only myopia induction (n=8). Peripheral irradiation consistently outperformed central irradiation in delaying axial elongation regardless of myopia induction status.

Effectiveness of central and peripheral red light irradiation at different energy densities

Previous research has shown that the bioactive range of red light irradiation is 0.001−0.10 J/cm². Currently, the mainstream commercial red light irradiation devices used for myopia prevention have an upper energy limit of 1.8–2.0 mW/cm². During preliminary experiments, we tried reducing the energy to one-tenth, which is 0.2 mW/cm², and found that the myopia prevention effect of central irradiation basically disappeared, but peripheral irradiation still had some effect. Therefore, we predict that 0.2 mW/cm² may be the lower effective energy limit for red light irradiation. So we used one-third as a reduction increment, setting three energy densities of 1.8, 0.6 and 0.2 mW/cm², to observe whether peripheral and central red light irradiation still have the effect of slowing axial length growth after energy reduction, and whether there is any difference in the effects between the two irradiation modes.

We tested irradiation at 1.8 mW/cm², 0.6 mW/cm² and 0.2 mW/cm² energy densities. Lower-energy densities coincided with decreased axial length control, yet peripheral irradiation remained more effective than central at the same energy density mode (figure 4).

Figure 4. Without myopia induction, the central irradiation at 1.8 mW/cm² and 0.6 mW/cm², and the peripheral irradiation at 1.8 mW/cm², 0.6 mW/cm², 0.2 mW/cm², can delay the axial elongation. Under the premise of myopia induction, central irradiation at 1.8 mW/cm², peripheral irradiation at 1.8 mW/cm² and peripheral irradiation at 0.6 mW/cm² can delay axial elongation. Lower-energy densities coincided with decreased axial length control, yet peripheral irradiation remained more effective than central at the same energy density mode.

Without myopia induction, the central irradiation at 1.8 mW/cm² and 0.6 mW/cm², and the peripheral irradiation at 1.8 mW/cm², 0.6 mW/cm² and 0.2 mW/cm² can delay the axial elongation. Under the premise of myopia induction, central irradiation at 1.8 mW/cm², peripheral irradiation at 1.8 mW/cm² and 0.6 mW/cm² can delay axial elongation, while central irradiation at 0.6 mW/cm² and 0.2 mW/cm², and peripheral irradiation at 0.2 mW/cm² cannot delay axial growth (figure 4).

Morphological changes of ocular tissues

No morphological changes in the cornea and lens were observed in all groups. Pathological analysis did not reveal significant apoptosis of retinal ganglion cells induced by red light irradiation, nor were there any morphological changes in the retinal choroid and sclera, compared with the blank group (n=8). It can be considered that 1 month of red light irradiation is safe.

OCT revealed a slight decrease in CCT in myopia-induced groups (n=8) compared with control (n=8), though not statistically significant. Both central (n=8) and peripheral (n=8) irradiation increased CCT, with peripheral irradiation having a more pronounced effect (figure 5).

Figure 5. OCT revealed a slight decrease in CCT in myopia-induced groups (n=8) compared with control (n=8), though not statistically significant. Both central (n=8) and peripheral (n=8) irradiation increased CCT, with peripheral irradiation having a more pronounced effect.

Discussion

Photobiomodulation with red light has emerged as a rapidly developing myopia control technology due to its significant efficacy,¹¹ yet its widespread clinical adoption is hindered by an incomplete understanding of its safety profile, leading to a divide between proponents and opponents. The key issue is how to avoid, or at least reduce, the potential risks associated with red light irradiation.

The exact mechanisms by which red light delays myopic progression are yet to be fully delineated, with hypotheses ranging from the activation of cytochrome C to enhance mitochondrial function and improve the bioactivity of irradiated tissues,¹²,¹⁴ to the thermal effect of red light promoting local blood circulation.¹⁵ Other molecular pathways, such as the NO pathway,¹⁶,¹⁸ are also under investigation. Without a complete understanding of these mechanisms, it is challenging to theoretically ascertain potential risks. Hence, clinical studies to explore risk mitigation strategies for red light therapy are necessary. Our study demonstrates that peripheral retinal red light irradiation effectively delays axial growth, and at the same energy density, it outperforms central irradiation, giving credence to the use of red light with lower-energy density and peripheral irradiation for myopia control.

Previous studies have demonstrated that the biologically active energy range for red light irradiation is between 0.001 J/cm² and 0.10 J/cm².¹⁹ In this experiment, each red light irradiation session lasted 180 s, potentially resulting in a biologically active red light energy density range of 0.006–0.6 mW/cm². Calculating based on a pupil diameter of 3 mm, the corneal plane energy density ranged from 0.07 mW/cm² to 7 mW/cm². Considering that the energy density of commercially available red light emission devices used for myopia control is generally less than or equal to 1.8 mW/cm², the highest energy setting used in this study was also capped at 1.8 mW/cm². Energy levels were reduced in steps of one-third, and the effects of myopia control were studied at three different energy densities: 1.8 mW/cm², 0.6 mW/cm² and 0.2 mW/cm². The study found that the effect of axial elongation delay decreased with the reduction in energy density. However, at each energy density level, peripheral irradiation consistently outperformed central irradiation. Under the premise of myopia induction, peripheral irradiation with a red light energy density of 0.6 mW/cm² still exhibited some effectiveness, whereas central irradiation at this energy density was ineffective in delaying axial elongation.

This study observed the effect of slowing axial elongation under different energy densities and irradiation patterns without myopia induction and found that both central and peripheral irradiation have a delaying effect on the emmetropisation process under normal conditions. These findings support the application of repeated low-energy red light irradiation for myopia prevention, especially considering the safety of low-energy peripheral retinal red light irradiation.

This study observed the effects of axial elongation delay under different energy densities and irradiation patterns without myopia induction, finding that both central and peripheral irradiations delayed the emmetropisation process in a normal state, similar to the results under myopia induction conditions. In the normal state, peripheral irradiation with the same energy density of red light was more effective in delaying axial elongation than central irradiation. This data provides a rationale for using low-energy red light peripheral irradiation in myopia prevention, especially considering that lower-energy peripheral retinal red light irradiation is very safe.

Previous studies demonstrated an increase in CCT following repeated low-energy red light irradiation,^{5 20 21} which is consistent with our findings. Despite the lower intensity of light received by the central choroid in peripheral irradiation mode compared with central irradiation mode, this study found that the increase in CCT caused by peripheral irradiation was greater than that caused by central irradiation. This finding suggests that the thickening of the choroid is not a simple consequence only in the irradiated area and that direct red light irradiation is not the sole reason for the increase in choroidal thickness.

Currently, commercial red light devices for myopia prevention all use central irradiation, where red light is mainly focused on the macular area. The macula is the most sensitive part of the retina. If the macula suffers photodamage due to red light irradiation, patients may experience permanent vision impairment. Nowadays, macula photodamage is the primary safety concern regarding the use of red light irradiation in myopia prevention and control. Previous studies²² indicated that using red light for 1 year does not lead to significant complications. However, data on the evaluation of longer-term safety and cumulative effects are not yet comprehensive. The long-term safety of red light therapy for myopia still requires further research. Logically, avoiding irradiation of the macular region and using lower-energy red light can help reduce long-term cumulative risks.

This study shows that peripheral irradiation can slow the development of myopia and is more effective than central irradiation. By using peripheral irradiation, the macular area can be perfectly avoided from light exposure, logically preventing photodamage to the macula. This can greatly alleviate current concerns about the safety of using red light irradiation to delay myopia, providing data support for the large-scale promotion of red light irradiation in myopia prevention.

Data availability statement

No data are available.