Energy Based Devices, Biologics, and Stem Cell Research for Dry Eye Disease

I often tell people that I did not start my medical career thinking that I would be a dry eye specialist. When I opened my clinic 28 years ago, straight out of residency, my focus was on general ophthalmology and a new specialty at the time – health and wellness. I invested in aesthetics technologies including intense pulsed light (IPL) to treat patients with skin conditions like rosacea. I discovered that IPL not only helped improve patient’s skin but also helped dry eye disease (DED).¹ I had several family members with DED – and I developed dry eye as well – so finding an effective treatment felt personal.

My experiences with aesthetics and DED have led me to the conclusion that DED is a skin and gland problem. Poor skin leads to meibomian gland dysfunction, which then leads to abnormal tear production.² When dealing with the skin, systemic disease, nutrition, age, hygiene, genetics, medications, and activities of daily life need to be considered. The physician must develop a holistic approach in caring for these patients. When we look at innovations that will combat DED, we have to separate the treatments into categories. The first category we will look at is technologies that treat the skin.

Energy-based Devices and Dry Eye

Energy-based devices (EBDs) can stimulate fibroblasts to produce collagen and elastin to improve the skin. I discovered that many EBDs can also improve the performance of the meibomian glands. For example, IPL has many mechanisms of action, such as killing microorganisms, stimulating heat shock proteins and fibroblasts, closing off abnormal telangiectasias, and photobiomodulating (PBM) cells.³ I believe that PBM is the most important mechanism of action for IPL. Red wavelengths of light stimulate mitochondria in the cells of the meibomian gland to function better. In turn, the glands can produce improved meibum.⁴

IPL and Dry Eye

We published a study demonstrating that IPL can lower the concentration of inflammatory mediators in the tear film of dry eye patients as well as improving the signs and symptoms of DED.⁵ It is now being shown that IPL may enhance the epigenetic pathways,⁶ which will be discussed later. I discovered the use of IPL for DED by treating rosacea patients.¹ These patients have a genetic condition that causes telangiectasias on the epidermis of the skin that produce inflammatory mediators that breakdown not only the skin but the meibomian glands as well. IPL improves the skin by closing off these abnormal vessels and a byproduct of IPL treatment for DED has been improved skin texture and appearance. After the age of about 28, the fibroblasts stop producing elastin and collagen, and IPL stimulates the fibroblasts to rejuvenate skin, effectively turning back the clock in the normal ageing process.

Low Level Light Therapy

Another EBD, low level light therapy (LLLT), utilises PBM but with light emitting diodes (LEDs), instead of a Xenon flashlamp like IPL.⁷ LED does not need doctor supervision and can be used at home since exposing the light to the naked eye will not cause any damage, unlike IPL light, which requires eye protection. LLLT can be used directly on the skin as well as via a mask at some distance from the skin. The further the light is from the skin, the less fluence is directed, causing less penetration into the dermis. LLLT directs, at best, a third of the energy of IPL and masks are less effective than direct contact LEDs. I have been able to patent the use of light devices for DED and developed an at-home LLLT device that patients have successfully used for over 10 years. ^8,9 A key fact is that red light is the wavelength that works best for photobiomodulating the meibomian glands.

Other Energy-Based Devices

Other EBDs to improve DED use heat directly on the skin to create microinjuries that improve skin texture and appearance when healed. These include radiofrequency (RF), fractional CO₂ laser, and plasma pens.¹⁰ Although these EBDs can be used to help improve DED, they do not directly stimulate meibomian gland cells like PBM technologies. Most doctors have used these technologies as an adjunct to IPL.

Radiofrequency uses electromagnetic waves in a frequency range of about 3 kHz to 300 GHz, generating resistive heat in tissues. It will generate enough heat in the dermis to melt viscous meibum. Doctors need to be careful as the heat generated can reach levels as high as 60ºC, which can cause burns, fat atrophy, and nerve damage around the orbit where the skin is thinnest.¹¹

Fractional CO₂ laser is an ablative resurfacing treatment that uses short pulsed light energy at 10,600 nm wavelength. We have had excellent results using the treatment on the lids for rejuvenation and temporary improvement in dermatochalasis. But could it help DED? We are currently conducting a study to see if the laser can reduce the symptoms of DED. The mechanism of action could be tightening of the lid by building collagen in the skin, increasing the force of the blinks, and increasing meibomian gland expression.

Tixel is a new device that uses heated titanium tips at 400ºC to create microchannels in the skin.¹² The tips are in the skin for eight milliseconds at a depth of 400 microns. Tixel is most like fractional CO₂ laser, since the skin is being penetrated with heat. Unlike the other EBMs mentioned, CO₂ and Tixel require anaesthetic cream prior to treatment, or patients will experience extreme pain. The physician should be well-versed in the complications of these devices because skin can react in various ways. For example, patients can experience post-inflammatory hyperpigmentation.¹² Postoperative management becomes important when administering penetrating treatments because, if handled incorrectly, the patient can be left with permanent scarring. Downtime is also needed with these procedures. Similar to other EBDs, Tixel improves signs and symptoms of DED. Time will tell where this fits into the DED treatment protocol. We have found better results with the CO₂ laser than Tixel, especially in patients with rosacea. A protocol I have used in the rosacea patient is to complete the IPL four-treatment protocol for DED and then a month later I will complete fractional CO₂ laser to the lids and face to close off remaining abnormal blood vessels.

Rexon, another EBD, has gained some attention employing low-power, high-frequency electric fields called quantum molecular resonance by the manufacturer to stimulate the meibomian glands to function better.¹³ Patients wear a mask that allows electrodes to contact the closed lids. The theory is that alternating the currents from 4 MHz to 64 MHz provides stimulation to the cells to work better.

Plasma pen uses electrical energy creating static that is transmitted onto the skin. An electrode from the pen creates an arc of plasma that generates heat from 60–100°C. A paper reported improvement of conjunctivochalasis after plasma-based conjunctivoplasty.¹⁴ Studies are ongoing to see if the use of plasma on the eyelids can improve dry eye disease. Periorbital post-inflammatory hyperpigmentation after plasma exeresis is a known adverse event from this treatment and doctors should be aware of the complication and know appropriate management.¹⁵

Optilift is a muscle stimulation device that directs radiofrequency to the periorbital muscles to improve lower lid tightness and blink efficiency.¹⁶ The platform is called Dynamic Muscle Stimulation (DMST). The treatment can be important in patients with lid laxity and a weak blink. When blinking we bring the lids together to squeeze the meibomian glands and achieve expression of the meibum. Lid laxity is a normal consequence of ageing but if you can stimulate collagen formation with these devices, it can improve skin tonicity.

Many different aesthetic treatments have been tried, hoping to replicate the success of IPL. I have been using IPL for DED for over 26 years with subsequent studies including an FDA approval study.¹⁷ The other treatments do not have as long of a track record and far fewer studies proving efficacy. I still have not found an aesthetic technology that matches the efficacy and all the benefits of IPL for DED.

Returning to my supposition that poor skin leads to meibomian gland dysfunction, which then leads to abnormal tear production, we should be more proactive in utilising all the tools at our disposal to keep skin healthy and stimulate the fibroblasts. Most important is to protect the skin from the damages of sun exposure. It can be as simple as the right sunscreen, a hat, topical antioxidants, and preventative EBD treatments.

Regenerative Treatments, Anti-Ageing, and DED

Platelet Rich Plasma

DED specialists are adopting regenerative treatments used for anti-ageing in other specialties to treat dry eye disease. Autologous serum drops have been used in eye care to treat cornea abrasions and dry eye.¹⁸ However, platelet rich plasma (PRP) is the blood product of choice in orthopedics, neurosurgery, and for anti-ageing specialties. PRP contains exponentially more anti-inflammatory mediators and growth factors than autologous serum.¹⁹

I started using PRP drops after a series of experiments to make an undiluted compound that could remain stable for the life of the drop. I was using PRP drops for dry eye disease, skin rejuvenation, cornea scarring, and lid injuries. I presented these uses and specific cases at the 2018 International Society of Ocular and Therapeutics (ISOPT) meeting.²⁰ Since this presentation several papers have demonstrated that PRP drops are helpful for the signs and symptoms of DED.²¹ But what I really wanted to know was, whether having more nerve growth factor could make a difference in pain. Many eye doctors combat eye pain with autologous serum eye drops, believing that these patients had abnormal cornea nerves because an inflamed tear over time could cause destruction. It wasn’t until extensive study of DED patients with cornea confocal microscopy (CCM) that we learned that DED also negatively impacts the cornea nerves.²²

Over time, as the demand for PRP has increased, the technologies to extract it have become better. I use PRP in my DED patients with neuropathic pain and, over the years, have continually upgraded to the newest PRP technologies, leading to an improvement in my PRP yield and results.

A growing number of DED patients are complaining of pain and allodynia. These patients have seen some doctors who have dismissed this pain as more psychological than physical because the symptoms outweigh the signs seen on the slit lamp or when measured with a Cohet-Bonnet aesthesiometer. CCM demonstrates that even patients with mild DED can exhibit serious damage to their corneal nerves. These patients have signs that correlate to their level of pain. This can be treated with nerve growth factor (NGF) from PRP or with the prescription purified NGF, cenegermin-bkbj (as Oxervate eye drops). I have demonstrated with CCM that the use of NGF can visibly regenerate nerves and patients report improvement in symptoms.

Now eye specialists, including our clinic, are utilising PRP as an injectable to the lacrimal and meibomian glands. Several studies have shown that the signs and symptoms of DED can be improved with injection into the lacrimal gland.²³ I am taking a slightly different approach. For years in our aesthetic clinic, we have micro-needled PRP into the skin to stimulate the fibroblasts to make collagen and elastin to improve texture and appearance of the face.²⁴ We have also used micro-needling of PRP to the scalp to spark hair growth. I am now micro-needling PRP to the skin around the meibomian and lacrimal glands, bathing these structures with PRP to improve function. Because we can choose the depth of our micro-needles, this may be safer than injecting directly into glands, which could possibly cause scarring of the tissue. The gauge of the needles is also smaller than what is used currently by doctors who are injecting the lacrimal gland. PRP contains insulin-like growth factor-1 (IGF-1) that can be used to stimulate cell proliferation and improved function.²⁵

Insulin

Besides PRP drops and Oxervate, some doctors have been utilising compounded insulin drops. The most common dosage reported in the literature ranges from approximately 0.1–1 IU/mL (often prepared from regular human insulin diluted in preservative-free artificial tears or balanced salt solution) and is administered two to four times daily. The proposed mechanism of action centres on insulin’s trophic and neuroregenerative effects on the ocular surface: insulin binds to IGF-1 and insulin receptors expressed on corneal epithelial cells and nerves, activating downstream PI3K/Akt and MAPK, signaling pathways that promote epithelial cell migration, proliferation, and survival.²⁵

Adrenocorticotropic Hormone

Another biologic that we have been using in severe DED, especially in patients that have systemic inflammation due to an autoimmune disease, is injectable adrenocorticotropic hormone (ACTH).²⁶ Currently we have two branded ACTH medications, Cortrophin and Acthar. As well as containing ACTH, they both contain other active peptides that stimulate the body to produce endogenous steroids and molecules that can bind melanocortin receptors (MCR). There are five MCRs in the body.²³ MCR2 is at the adrenal cortex and that is how the steroid is produced. The half-life of the steroid is about 17 hours. The other MCRs are connected to cells responsible for inflammation, such as T cells, NF-kB, and macrophages. ²⁷ The medications bind to these receptors and downregulate their production, decreasing inflammation. In our practice, we inject our patients 80 units, twice a week for 90 days. The goal is to calm an acute inflammatory flare, enabling the other treatments to work better. We now know that these patients with systemic disease can have a cytokine storm that can manifest in worsening DED signs and symptoms.

We recently published a study looking at 12 patients with signs and symptoms consistent with severe DED.²⁶ These patients had various treatments but still had, on average, with one patient who had a score above 90. These patients went through a 90-day protocol of 80 units of Acthar twice a week. We demonstrated a clinically significant improvement of the signs and symptoms of DED.²⁶ This medication is especially helpful in patients with DED and pterygium. These patients normally have a higher rate of recurrence. I find pretreating them before surgery for one month and then two months after surgery reduces the inflammation and recurrence rate.

GLP-1s

We are currently studying how the glucagon-like peptide receptor agonists (GLP-1s) are helping our DED patients. In a small pilot study, we found that DED patients on GLP-1s have a reduction in the signs and symptoms of DED.²⁸ This can be attributed to a decrease in systemic inflammation, weight loss, and improvement in insulin resistance.²⁹ We have seen an increased focus on the gut-eye axis. Many papers have shown that an acidic gut leads to systemic inflammation and disease.³¹ After collecting stool samples on DED patients, I discovered that the majority of DED patients had dysbiosis, an imbalance of microbes in the gut.

The Importance of Diet and Supplements

The focus of my last book, The Toyos Dry Eye Diet, demonstrates how a specific non-inflammatory diet can improve the signs and symptoms of DED.³⁰ Diet can be used in conjunction with the treatments named above to enhance the effect. In my experience, most DED patients are eating inflammatory foods that exacerbate meibomian gland dysfunction.

I also recommend supplements. The supplement market is filled with pseudoscience, so I have only recommended products that have been studied and validated. Since we are focusing on innovations, we can’t ignore the science of supplements that stimulate mitocochondrial function. CoQ10 is a coenzyme needed to power our mitochondria.³² It is also an antioxidant that regenerates vitamin C and E. My belief is that DED patients can benefit from supplementation because we are trying to jump-start the cells responsible for making natural tears. Certain medicines, such as statins, rob us of CoQ10.³³ CoQ10 may have some neuroprotective effects and has been used in glaucoma.³⁴

Dimethylglycine (DMG) is an essential amino acid, an antioxidant and mitochondria booster. Choline is metabolised into DMG. You can find choline in several foods – beans, grains, pumpkin seeds, and liver. We need more research, but we do know that DMG is found in lower amounts in patients with the disease.³⁵ It is also found in higher quantities in fetal blood than maternal blood, leading researchers to believe that it is needed in development.³⁵ Choline is necessary for normal ocular function including tear production.³⁶

Other supplements and medications that deserve a mention, and will lead us to our last topic of using regenerative science to help with DED, are nicotinamide adenine dinucleotide (NAD), astragalus, metformin, and resveratrol. We are in an incredible time because ageing is now being viewed as a disease that can be conquered and funding for research is at an all-time high.

Most of the research centers around epigenetics. Our DNA is static and written in the code of base pairs. The DNA is wrapped around proteins called histones. We have proteins that regulate when a particular gene is turned on and off. We also have proteins that repair our DNA. Lastly, we have caps at the end of the chromosome that protect our DNA called telomeres. The shorter your telomeres, the lower your life expectancy.³⁷ The interaction of all of these components of our DNA encompasses epigenetics.

Can We Use Genetics Knowledge to Improve DED?

Nobel Prize-winning work done by Elizabeth H Blackburn, Carol W Grieder, and Jack W Szostak demonstrated that we can use the telomerase enzyme to lengthen our telomeres and possibly increase lifespan.³⁸ Shortened telomere length is associated with cardiovascular diseases, stroke, cancer, arthritis, osteoporosis, cataracts, type 2 diabetes, hypertension, mental diseases, chronic obstructive pulmonary disease, and dementia. Also, shorter telomere length leads to decreased cell growth and increased cell death.³⁸ A healthier lifestyle can activate telomere length. I am convinced that improvement in telomerase activity will improve DED. (The Chinese herb astragalus can stimulate telomerase.³⁹ Astragalus is in my must-have supplements list.)

Are There Other Supplements and Lifestyle Changes that Can Help with DED?

Epigenetics is focused on seven enzymes called sirtuins (named after the yeast SIR2 longevity gene Silent Information Regulator), which are responsible for regulating histones and for turning on and off certain genes.⁴⁰ These proteins need NAD to function. If we want to be healthy and improve our DED, we need to keep our sirtuins doing their job of DNA repair.⁴⁰

NAD is important for normal functioning of the mitochondria, the powerhouse of our cells. We know that NAD levels decrease with age. Basal tear secretion also decreases with age. It is not a great leap to think that increasing the NAD in our system will help the meibomian glands work more efficiently.⁴⁰ IPL and LLLT work because the wavelengths of light at a specific fluence (power) stimulate the mitochondria of the meibum cells to work better. Patients that I have supplemented with NAD have improved more rapidly with IPL than patients with IPL alone. This is another reason why younger patients responded more quickly to IPL than older patients: their levels of NAD are naturally higher. DED patients need activated sirtuins to repair their diseased goblet cells, meibomian, and lacrimal glands.

A gene that also affects health and longevity is , the mechanistic target of rapamycin. mTOR is responsible for DNA repair and digesting old proteins, autophagy, and can be used for cell growth and repair.⁴¹ When amino acids are in abundance to make proteins, mTOR activity is spent on growth. When nutrients are scarce, mTOR activity is spent on repair and survival. This knowledge is behind the thought of intermittent fasting or calorie restriction to inhibit mTOR.⁴¹ When mTOR is inhibited by calorie restriction or by rapamycin, the body goes into survival mode, shutting down activity in the body that is not necessary. When mTOR is suppressed, it will signal the body to begin the process of autophagy (Greek for eating of oneself), breaking down and removing dysfunctional cellular components to conserve energy.

Adult tissues have stem cells, undifferentiated cells that can regenerate and differentiate into a specific needed cell type. However, as we age, these stem cells can accumulate mutations and lose their ability to function properly. This is where mTOR becomes an important factor in the rejuvenation of these stem cells by initiating repair.

Anti-ageing science has shown us that stress that doesn’t kill us makes us stronger. Hormesis is a biological process where stressors induce a beneficial effect.⁴² I didn’t need this research to prove to me that shocking cells could improve their condition. Our aesthetics clinic had long provided different treatments that shocked the skin to rejuvenate it

Activating Sirtuins and mTOR

On the lifestyle front, exercise and diet can activate the longevity genes. I have already recommended NAD and astragalus but patients can also take resveratrol.

Professor Konrad Howitz found that butein – a polyphenol, found in strawberries and flowering plants – can activate SIRT-1.⁴³ Resveratrol has the same chemical structure as these, and is found in grapes. Plants have stress molecules, as we do, and grapes produce resveratrol when stressed. Pinot Noir wine is produced in a stressed soil and is the wine that produces the most resveratrol.

These molecules from the plant world are called xenohormetic. Other xenohormetic plants and molecules are metformin from lilacs, epigallocatechin gallate from green tea, and quercetin from fruit. I recommend these xenohormetic foods to my patients.

Metformin is a prescription drug used to treat diabetes. The benefits of taking metformin for general health are many. Metformin can help mTOR by aiding in calorie restriction, it can activate the metabolic control enzyme known as AMPK (AMP-activated protein kinase is a cellular energy sensor when turned on can improve mitochondrial function), and has anti-inflammatory effects.⁴⁴ It has been suggested that metformin could be a treatment for dry eye disease but more research is needed.

Future Innovations in DED

I believe the future lies in gene therapy and stem cell science. All the treatments that I named are trying to change a genetic predisposition to ageing skin and glands that cause dry eye. Inflammation that DED patients experience is prematurely ageing their glands. We are gathering all the science and technology that we have to restore healthy gland function to achieve normal tear production. Artificial tears are trying to replace a natural tear that has 2,000 essential elements that create adequate homeostasis of the eye. Some topical drops are beneficial in decreasing inflammation and evaporation. We now have nasal and topical medications that can stimulate a natural tear, but if the glands are dysfunctional then the tear is not entirely normal. These medications are important to bridge the gap between the now and the future. But the future is already here.

Recently mice with damaged retina cells were given Yamanaka factors that rejuvenated the cells.^45,46 What are Yamanaka factors? Shinya Yamanaka is a Nobel Prize winning surgeon that discovered transcription factors that could turn fibroblasts into to stem cells.⁴⁶ The four transcription factors are OCT4, SOX2, KLF4, and c-MYC.¹ The stem cells can be reprogrammed into pluripotent stem cells, iPSCs. You can see the possibilities for DED in patients that have damaged lacrimal and meibomian glands, or goblet cells. It could be possible that you can administer Yamanaka factors and regenerate these cells restoring normal tear function. The downside is that c-MYC can overexpress and cause tumor formation. Where we can start is stimulating the fibroblasts, like Yamanaka, to produce collagen and elastin on the face.

Conclusion

There are many factors that contribute to DED. The holistic approach to treatment is the most efficacious. What I enjoy about DED is that it is a new specialty and we have much to learn. Also, it incorporates all of my interests – aesthetics, anti-ageing, nutrition, ophthalmology, and research. I caution doctors to not be quick to dismiss an idea, no matter how foreign, because it could be the game changer. I met resistance from the medical community when I introduced light as a treatment. Skepticism in medicine is important, but I also learned from Linus Pauling, who gave that lecture that was such a turning point for me in university. He said, “Science is the search for truth, that is the effort to understand the world: it involves the rejection of bias, dogma, revelation.”⁴⁷ If we understand that we need to widen our outlook for treatments to help our DED patients, we can discover something new and innovative.

Rolando Toyos MD is an American physician and medical director who specialises in ophthalmology. He developed the use of intense pulsed light (IPL) and low-level light for the treatment of dry eye conditions such as meibomian gland dysfunction.

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