Photobiomodulation in ocular therapy: current status and future perspectives

INTRODUCTION

Light therapy has been known to have therapeutic effects for a long time. This phototherapy involves the application of sunlight or artificially generated light of certain specific wavelengths aimed at the targeted region of the body. Phototherapy has been proven to treat various health conditions including inflammatory diseases, infectious diseases, and diseases related to optics and seasonal affective disorders^[1]. Among light wavelengths, red light is most prominent concerning therapeutic applications and has been implemented since contemporary times with the title of low-level laser energy or photobiomodulation (PBM). Red light is composed of longer wavelengths and lesser frequency^[2]. The specific wavelengths utilized in photobiomodulation are far-red to infrared. Either a laser or light emitting diode is used to omit the wave rays of wavelength around 600 to 1000 nm. Due to the larger wavelength, these waves can penetrate the body tissues. Current applications of the PBM system involve facilitation in wound healing by repairing the damaged tissue, improvements in cardiac conditions, improvement in neurological pains, and nerve repair after injury^[3].

PBM has a wide range of applications in the field of ophthalmology. Wavelength suitable for optical operations falls under the range of visible to near-infrared region. Typically employed wavelengths for the retina include 630 nm from red light area and 850 nm from near-infrared region^[4]. However, the value of wavelength may vary depending on the therapeutic effect desired. For example, a wavelength 600-700 nm is specific and effective in targeting superficial layers within the retina, while on the other side, a higher wavelength of around 800 to 900 nm can deeper penetrate within the eye tissues. The targeted function of light in the retina is to promote the cellular processes in beneficial ways in retinal disease conditions such as retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy^[5].

Different cellular processes are targeted by the light at specific wavelengths. For PBM of the retina, red to near infrared (NIR), the targeted region is mitochondrial proteins specifically cytochrome C oxidase (CcO). A cascade of events is initiated by the activation of CcO. Activated CcO increases the bioproduction of energy reservoir adenosine triphosphate (ATP)^[6]. It also promotes the downregulation of harmful oxidative species from the cell and promotes antioxidant stability. As a result, the cellular processes are restored to normal. Restoration is observed in different forms such as regulating gene expression, calcium signaling, and activating transcriptional factors^[7]. Moreover, different pathways associated with cell death and inflammatory reaction are also regulated as illustrated in Figure 1.

The human eye is designed to capture light through receptors and convert light energy into electrical signals which are being executed by the brain to form images. The organ responsible for this transformation is the retina. The first step in phototransduction is carried out by photoreceptors in the retina which convert specific wavelengths into neural signals^[8]. Light striking initiates a series of biochemical reactions involving multiple enzymes and coenzymes within the mitochondria of cells in the retina which initiate nerve signals in the brain. Signals from rods and cones of the eye are processed by different types of neurons in the brain and are expressed in the form of action potential in the ganglia of those retinal cells whose axons are associated with the formation of the optic nerve^[9]. Since the retina is entirely dependent upon the precise supply of light energy and any alteration in the supply of energy is related to the mitochondrial damage, hence retina appears to be a potential therapeutic target for photo biomodulation^[10].

Research has been carried out to find the therapeutic impact of PBM in optical diseases and preclinical studies have shown that PBM therapy has the potential to hinder cell death, reduce the number of reactive oxygen species and reactive nitrogen species, and promote the balanced immune responses in retinal cells against any physical or biochemical damage^[11]. An in vivo study results showed the PBM is effective in reducing oxidative stress, hyperoxic stress, age-related alterations, and retinopathy in the retina. At the molecular level, genes and proteins involved in producing inflammatory responses are modulated and as a result, there is a decrease in the production of mediators like C2a nd C3a^[12] .

HISTORY

The therapeutic effect of PBM is attributed to Ender Mester, who is considered as the father of PBM. In his experiment in 1967, he used low-level red waves to treat tumor cells in rat models. Although he could not find any progress in tumor treatment, he observed increased hair growth and more specifically the regrowth of hair in the targeted area imposed by the exposure of light rays^[13]. The potential of PBM sparked interest and certain other experiments were also conducted in which red light was shown to heal various wounded areas. It is not wrong to say that red light stood promising therapeutic benefits in history. Certain other notable milestones of red light in history involve the work of Finsen in the 18^th century. Niels Fensen utilized red light with longer wavelengths to treat certain skin conditions^[14]. He cured small blisters present on the skin by targeting them with red and near-infrared wavelengths. He also treated lupus vulgaris by targeting the lesions with ultraviolet radiation. These therapeutic findings were a big milestone pointing towards the potential of red light in medicine and hence he is termed the “Father of Contemporary phototherapy” and also won the Nobel Prize in 1903^[15].

With the passage of time and advancements in scientific research, more therapeutic aspects have been discovered about PBM. The therapeutic aspects are diverse, ranging from one type of treatment to another in another part of the body. Such effects have been observed by in vivo studies conducted in animal models as well as in clinical studies involving disease patients. The range of therapeutic effects involve wound healing, alleviating pain, cognition, cancer as well as diabetes^[16]. It also heals and accelerates the recovery phase of tissues post injury such as peripheral tissues and retinal tissues and in worse cases, it helps to better alleviate traumatic brain injury. Other than above mentioned therapeutic aspects, there are many retinal approaches as well which are discussed in this literature review. Few of the highlighted retinal conditions include diabetic retinopathy, amblyopia, age related macular degeneration^[17].

MECHANISM OF ACTION

The mechanism of action of PBM is entirely different from the previous conventional laser techniques. Earlier techniques primarily relied upon thermal mechanisms of either heating or cooling to treat certain medical conditions such as tissue ablation, coagulation, photocoagulation, and skin healing. However, some of the side effects are associated with the excessive use of thermal-based laser techniques such as pain and discomfort during the treatment, partial and temporary redness in the target area, and bruises and infection in rare cases^[18]. PBM uses red light of wavelength range between 630 to 1000 nm with low intensity to treat the targeted area. During the late 1980’s and 1990’s scientists already started identifying the mechanism of action of laser light upon cells and indicated that main target within cellular structures is mitochondria. CcO is a large transmembrane protein complex and functions as the primary acceptor of light energy into the mitochondrial compartment^[19].

CcO plays an integral role in the electron transport chain of energy production in mitochondria. The enzyme assists in the shift of electrons from cytochrome to the end acceptor i.e., molecular oxygen. Research in this field suggested that CcO is the primary mediator of electron transport chain and vital photoreceptor as maximum efficiency was observed in this region in action spectrum (Figure 2).

Different tests conducted with cell cultures of primary neurons, HeLa cells and animal models of rat emphasize the importance of CcO for PBM. As the cells were exposed to red light with wavelength around 670 nm, they inhibit the production of tetrodotoxin and increases the production of CcO. The reason is that since tetrodotoxin acts in such a way to block production of CcO, a decreased level of it will automatically upregulate CcO in primary neuron cells.

Not all wavelengths of light are protective. Light with shorter wavelengths such as the blue light can induce damage in eyes especially retinal cells. A study was conducted with rat models of light-induced retinal degeneration. The study aimed to evaluate the impact of longer wavelength light rays on retinal recovery. The light waves were used at the wavelength of 670 nm. Treatment has a clear positive effect on the Müller cells in the retina. A few of the obvious beneficial changes in Müller cells reported were increased preservation of cellular structures, a clear decrease in stress and elimination of gliosis. Another important finding of the study showed there was a balanced metabolic state of Müller cells since glutamine synthetase was continuously being produced by the cells. In addition to this, Müller cells are a key component in reducing the inflammatory changes in the cells. Inflammation leads to the immune responses by the cells which triggers the disease progression. Decreasing inflammation provides a solution to hinder disease progression. Another important aspect with respect to the Müller cells is these cells are involved in reduced activation of NO and pretreatment with PBM at 670nm is helpful in downregulating the tumor necrosis factor (TNF) production which in turn reduces the production of NO enzyme and ultimately an overall decrease in reactive NO species^[27].

PHOTOBIOMODULATION IN OCULAR DISEASES

CONCLUSION

Overall, the application of PBM appears to be a promising and innovative medical intervention for treating ocular conditions. It possesses the potential to treat a variety of retinal diseases. In this review, the therapeutic potential of light therapy is being discussed, as how a specific wavelength spectrum can penetrate the cell membrane of retinal cells and target specific sub-cellular structures without imposing any potential damage and hence stimulate the cellular energy production and reducing harmful effects such as inflammation and oxidative stress. Since long ago, PBM has been in medicinal practice and a lot of research has been carried out to understand the underlying mechanism of action of red light on retinal cells. It is stated that mitochondria and enzymes of electron transport chain are targeted specifically CcO and it results in overall upregulation of energy production. Processes of calcium signaling gene expression and inflammation are modulated and could be considered as target pathways to bring out further therapeutic potential of PBM. Clinical studies have provided clear evidence for the effectiveness of PBM in treating patients with visual acuity, increased retinal thickness, and other ocular disease symptoms. The potential of PBM ranges from non-invasive and target specific to a technique with minimum side effects. In future, PBM therapy signifies a milestone in medicine in combination with advanced techniques, extensive clinical testing and profound research. In future, PBM will be used as combinational therapy and will be focused at more specifications such as target-specific treatment, combination of personalized medicine with molecular techniques. Furthermore, longitudinal studies should be carried out to find out the chances of any long-term side effects. Further, for availing the future potential of PBM, a collaborative effort among researchers, engineers and clinicians is required to harness full scope of this light therapy. With this collaborative approach, PBM is expected to come up as a milestone for treating ocular diseases and new hopes and possibilities for patients across the globe.