REGENERATIVE MEDICINE – RENEWED HOPE FOR DRY EYE DISEASE SOLUTION

PRODUCT SPOTLIGHT - STIMULEYES™

By Deborah Kotob, ABOM

Release Date: January 1, 2022

Expiration Date: December 31, 2022

Learning Objectives:

Upon completion of this course you should understand:

  1. Provide the definition of Dry Eye Disease (DED).
  2. Define the tear film layers and their function, and describe the reasons for tear film instability.
  3. Describe the consequences of tear film instability.
  4. Describe prevalent treatment methods.
  5. Explain how regenerative eye drops, such as StimulEyes™, focus on reducing inflammation and providing the growth factors which may improve positive outcomes beyond short term symptomatic relief.

Course Description

Are you one of the estimated 45 million Americans who suffer from chronic dry eye disease (DED)? The probability is that you suffer from or know others living with this multi-factorial progressive condition. In this course, we will learn how regenerative eye drops, such as StimulEyes™, focus on reducing inflammation and providing the growth factors which may improve positive outcomes beyond short-term symptomatic relief.

Credit Statement:

This course is approved for one (1) hour of CE credit the American Board of Opticianry (ABO). One hour, Ophthalmic Level 2, Course STWJHI047-2.

This course is approved for one 1 hour Dual CE credit by NYSSO

Support

THIS COURSE IS SUPPORTED BY AN EDUCATIONAL GRANT FROM M2 BIOLOGICS

Are you one of the estimated 45 million Americans who suffer from chronic dry eye disease (DED)? The probability is that you suffer from or know others living with this multi-factorial progressive condition.

The frustration with ineffective treatments is enough to bring those with chronic dry eyes to tears! However, do not confuse reflex tears when you cry with the basal tears that protect the ocular surface and keep the cornea clear for visual clarity. Today we are addressing the quality and quantity of basal tears and the link to dry eye disease.

Dry eye affects young and old. While we see an upsurge in young digital natives experiencing dry eye, the risk, complications and severity increase with age. Most of us self-medicate with over-the-counter eye drops but as the disease advances, we visit our ECP desperate to find a permanent solution to end our eye irritation and pain. The discomfort we experience from dry eyes degrades our quality of life and can ultimately affect our vision. Sadly, most early-stage dry eye sufferers leave their ECP office with lubricant eye drops, which only provide short-term symptomatic relief. Dry eye disease is progressive and multifactorial with causes ranging from chronic blepharitis, meibomian gland dysfunction, lid and tear film abnormalities. Tear film abnormalities can cause too much of the wrong kind of tears, or too little quality tears. A healthy tear film nourishes, protects and lubricates the eye to maintain the homeostasis of the ocular surface. In this course, we will learn about a regenerative biologic eye solution—a new and exciting frontier to help dry eye disease sufferers potentially restore their ocular surface to a healthy status.

“We treat the cause not the symptoms” is an idiom frequently heard, yet symptom relief is often the only treatment available in chronic diseases, like DED. While short-term relief of symptoms is priority when suffering, what we really want is long-term relief and to live life unencumbered by dry eye symptoms. DED is a chronic disease that in advanced stages can lead to eye inflammation, abrasion of the corneal surface, corneal ulcers and vision loss. Prevalent DED treatments provide temporary relief of symptoms by lubricating the eye to relieve discomfort, while other treatments reduce inflammation that contributes to cell, gland and corneal dysfunction and damage, thereby slowing the progression of the disease to advanced stages. The foundational components in StimulEyes have produced restorative effects on wounds, burns, pulmonary disorders, and diabetic, venous and arterial ulcer ations. This success in treating other conditions exemplifies the promise StimulEyes may hold for restorative outcomes in the treatment of DED. This course introduces StimulEyes, a break through, chemical-free biological fluid (eye drop) treatment for DED from M2 Biologics.

WHAT IS DRY EYE DISEASE (DED)?

“Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” –TFOS DEWS II

Dry eye disease is one of the causes involved in the dysfunction of the integrated structures of the ocular surface:

• Lid margin disease consists of blepharitis and meibomian gland dysfunction.

• Blink dynamics or blink Lagophthalmos is incomplete blinking.

• Tear deficiency or healthy tear film disruption.

• Corneal integrity or keratoconjunctivitis sicca.

• Topographic surface disorders such as pinguecula/pterygium, basement membrane dis ease or conjunctivochalasis.

• Other: allergy, infection.

The lacrimal function unit (L.F.U.), an integrated system consisting of the lacrimal glands, ocular surface and lids, as well as the sensory and motor nerves/connections, preserves the integrity of the tear film along with corneal transparency and visual quality. The L.F.U. regulates the major components of the tear film in response to environmental, endocrinological and cortical influences. While disease or damage to any component of the L.F.U. can result in dry eye, the core mechanisms of dry eye are driven by tear hyperosmolarity and tear film instability. (aao.org/ eyenet/article/the-tfos-dry-eye-workshop-ii Accessed 8/31/2021)

“Tear hyperosmolarity arises as a result of water evaporation from the exposed ocular surface, in situations of a low aqueous tear flow and/or as a result of excessive evaporation.” (“The Definition & Classification of Dry Eye Disease - Guidelines from the 2007 International Dry Eye Workshop”)

The tear film is comprised of layers that overlay the conjunctiva and cornea. Traditionally the tear film is described as consisting of three layers, lipids, aqueous and mucin (LAM).

Lipid: The tear film outer oily layer is produced by meibomian glands in the lower and upper eyelid margins. This oily layer smooths the eye’s surface and keeps tears from evaporating too fast and helps them adhere to the eye surface.

Aqueous: The tear film middle layer is the aqueous—a watery layer produced by the lacrimal glands. The aqueous nourishes the cornea and the conjunctiva. This watery layer cleans the eye and flushes out foreign particles or irritants that are wrapped up by the other major component, mucin.

Mucin: The goblet cells of the conjunctiva, as well as the surface cells of the cornea and the conjunctiva, produce this protective lubricant of tears. It helps spread the watery layer of tears across the eye to keep the eye wet, and it traps and wraps up foreign pathogens and debris so they do not damage the ocular surface.

Note: TFOS DEWS II depicts the tear film as a two-layered interactive structure composed of a mucoaqueous layer and a lipid layer, which they define as follows: “The mucoaqueous layer serves to reduce friction and provide hydration to the ocular surface, while the lipid layer serves to decrease surface tension and minimize evaporation and tear film instability. Each blink drives capillary movement and upward drift of the lipid and mucoaqueous layers, which contribute to proper tear distribution across the corneal and conjunctival surfaces.”

Dry eye disease is classified by the National Eye Institute as an evaporative or aqueous deficiency dry eye.

Evaporative Dry Eye (EDE) is caused by the underlying condition meibomian gland dysfunction (MGD). MGD occurs when the meibomian glands fail to excrete healthy oily lipids to the composition of the tear film, without which the tear film does not smoothly coat the eye with every blink and tears won’t adhere to (stay-on) the eye surface. If the meibomian glands do not contribute enough oily liquid to the tear film, it evaporates too fast, leading to evaporative dry eye. Meibomian gland dysfunction is cited as the number one causal factor in evaporative dry eye disease.

• Intrinsic EDE is caused by meibomian lipid deficiency, poor lid congruity and lid dynamics, low blink rate and certain medication side effects from such drugs as retinoids, antihistamine, etc.

• Extrinsic EDE is caused by etiologies that increase evaporation due to their pathological effects on the ocular surface such as Vitamin A deficiency, toxic topical agents such as preservatives, contact lens wear and a variety of ocular surface diseases including allergies.

Aqueous Deficiency Dry Eye (ADDE) occurs when the lacrimal glands fail to produce adequate aqueous fluid. When the cause of dry eye is a failure of the lacrimal glands to produce enough watery fluid to keep the eyes adequately moistened, the condition is aqueous deficiency dry eye.

ADDE has two subclasses:

1. Sjogrens Syndrome Dry Eye (SSDE) is an exocrinopathy in which the lacrimal and salivary glands, as well as other organs, are targeted by an autoimmune disease, and

2. Non-SSDE most commonly presents as Age-Related Dry Eye (ARDE).

Dry Eye has many different names: dry eye syndrome, dry eye disease, ocular surface disorder or simply “dry eye,” and it is also described with the following medical terms:

• Keratitis sicca: Describe dryness and inflammation of the cornea.

• Keratoconjunctivitis sicca: Used to describe dry eye that affects both the cornea and the conjunctiva.

• Dysfunctional tear syndrome: Poor quality of basal tears is as detrimental as low basal tear quantity.

DRY EYE DISEASE CONVENTIONAL TREATMENT

• Artificial tears—drops, sprays, gels, ointments, slow-release pellets are used to replace deficient tears with artificial tears and lubricating eye drops to reduce discomfort and coat and protect the cornea from abrasion. In “The Modern Approach to the Treatment of Dry Eye, a Complex Multifactorial Disease,” Aragona P, Giannaccare G, Mencucci R, et al, state: “Tear substitutes have been traditionally used for the treatment of DED symptoms. However, it is important to note that tear substitutes are not specifically designed to improve symptoms, but to prevent their buildup. Consequently, they should be instilled regularly throughout the day to avoid symptom aggravation and not used on an as-needed basis. It is also important to consider that some eye drop formulations may contain preservatives, which have the potential to adversely affect the ocular surface and induce noxious symptoms. In these situations, it is important to limit their long-term use.”1

• Punctal occlusion (plugs or cautery) reduce tear drainage to facilitate tear retention.

• Clear obstructed meibomian glands and restore the flow of healthy lipids into the tear film.

The two methods to express:

1. Meibomian gland probing (faster and more complete relief of symptoms experienced). When combined with corticosteroid eye drops, acted faster and provided more complete eye relief of symptoms.

2. Thermal pulsation system heats and liquefies the waxy meibomian gland buildup. Then pulsating pressure clears the glands. While these treatments are very successful in the short term, it does not address the underlying gland dysfunction cause and will need to be repeated periodically.

• Anti-inflammatory: Inflammation of the ocular surface is a vicious cycle where chronic dry eye leads to inflammation, and inflammation leads to dry eye. Chronic dry eye is recognized as a chronic inflammatory disease and as such, anti-inflammatory drugs are prescribed to block the immune response that triggers inflammation. Suppressing the inflammatory response in the glands and cornea facilitates the ocular surface return to a healthy tear film. Some of the anti-inflammatory drugs used to treat dry eye include: antibiotics, corticosteroids, cyclosporine (immunomodulatory – immunosuppressant) and Lifitegrast. Topical cyclosporine, with or without corticosteroid drops is used to increase tear production in people with dry eye disease. Cyclosporine is in a class of medications called immunomodulatory. It works by decreasing swelling in the eye to allow for tear production.

Corticosteroids treat inflammation and relieve symptoms such as swelling, pain, redness or irritation; sometimes used following eye surgery or an eye injury.

New dry eye disease treatment is regenerative. Regenerative treatment has the potential to accomplish all of the above and more. The hope for regenerative treatments like StimulEyes is to treat the symptoms in conjunction with the cellular repair potential derived from growth factors.

INTRODUCING STIMULEYES

First, what is regenerative medicine? Regenerative medicine may be defined as the process of replacing or “regenerating” human cells, tissues or organs to restore or establish normal function. This field holds the promise of regenerating damaged tissues and organs in the body by stimulating the body’s own repair mechanisms to heal tissues or organs. Regenerative medicine may also enable scientists to grow tissues and organs in the laboratory and safely implant them when the body is unable to heal itself. Current estimates indicate that approximately 1 in 3 Americans could potentially benefit from regenerative medicine. Most associate regenerative medicine with stem cells. However, the study of stem cells has advanced new methodologies. There are no claims of live stem cells in the final StimulEyes product. Even in the absence of stem cells, the StimulEyes amniotic fluid matrix—with its various bioactive proteins and growth factors— offers the potential of relief, repair and the possibility of a return to a more normal function. Newer regenerative medicine is made with many natural elements known as “biologicals.” Biologicals do not present the moral, ethical or religious concerns of stem cell harvesting that confronted the field in the past. The human body is loaded with stem cells and progenitor cells (partially complete cells). The elements forming the matrix of StimulEyes are comprised of hyaluronic acid for lubrication, protein cytokines for their antiinflammatory action, and growth factors for their cellular repair potential. Together, the mechanisms of action of these components offer the impressive potential for results seen with regenerative medicine. (M2 Biologics)

SYMPTOM RELIEF AND REGENERATIVE PROPERTIES OF AMNIOTIC FLUID (AF)

The primary indication for use for StimulEyes is the treatment of Dry Eye Disease. The potential etiology of DED is multifactorial ranging from environmental to gland malfunction, disease, hormonal alteration and medicine use.

The amniotic fluid matrix is the basis for the efficacy of StimulEyes biologic eye drops. The matrix’s components treat the short-term symptoms and may potentially return the ocular surface to a functional healthy status.

Amniotic fluid provides the fetus with biomolecules containing proteins, lipids, carbohydrates, hormones electrolytes, minerals, vitamins and antibodies from the mother2; proteomic analysis revealed that AF is composed of a huge variety of proteins ranging from enzymes to structural proteins, heat shock proteins as well as signaling molecules3. Moreover, AF contains anti-microbial peptides and factors4. These anti-bacterial properties are retained post-processing5. The nutrientrich and anti-pathogenic nature of AF makes it an excellent biomaterial for promoting cellular growth and wound healing.

A recent study examined a proprietary AF solution “FloGraft™” in treating patients with severe dry eye disease6. Two strategies were employed: 1. Soft contact lenses were soaked in FloGraft for 30 minutes before being placed into patients’ eyes for one week, and 2. Artificial tears were mixed with FloGraft and were applied to patients’ eyes four times a day for one week. With both methods, patients reported improvements in terms of symptomatic relief or showed a decrease in the distribution of punctate staining (indication of corneal epithelial injury) or both. Notably, no negative side effects were described, indicating AF’s safety and efficacy in treating DED in vitro. AF was shown to induce an upregulation of Rhodopsin and Thy-1, which marks for rod photoreceptors and retinal ganglion cells respectively, therefore suggesting that AF was able to promote trans-differentiation of retinal pigment epithelial cells (RPE) into neuro-retinal cells. AF treated cells were also able to show robust cellular proliferation and minimal cell death7, adequately illustrating its pro-growth and anti-apoptotic properties.

STIMULEYES COMPOSITION

The amniotic fluid components in StimulEyes have the potential to utilize and enhance the cells present in the eye and their function. Anti-inflammatory and immunomodulatory cytokines have the potential to reduce inflammation. Growth factors aid in healing, repair and regeneration. Hyaluronic acid lubricates and protects.

Bio-proteins—Cytokines, a large group of proteins secreted by cells to signal and regulate immunity, inflammation and hematopoiesis (formation, development and differentiation of blood cells). For patients, the potential reduction of inflammatory processes holds significant benefit.

Hyaluronic acid—A viscous glycosaminoglycan found in umbilical cord blood, vitreous humor, synovial fluid, amniotic fluid and distributed widely throughout connective, epithelial, neural tissues. It serves primarily as a lubricant and may provide one of the first signs of DED eye irritation relief.8

Growth factors which stimulate cellular growth and differentiation:

• EDF – Epidermal Growth Factor
• PDGF – Platelet Derived Growth Factor
• TGF, Beta 1 – Transforming Growth Factor
• bFGF – Fibroblast Growth Factor
• ANG-2 – Angiopoietin 2
• VEGF – Vascular Endothelial Growth Factor
• MMP-9 – Matrix Metallopeptidase 9 tissue stimulating tissue remodeling
• TIMP 1,2,3,4 – Tissue remodeling
• IL 10-and IL-1ra – Anti-inflammatory activity
• MPO – Myeloperoxidase, antimicrobial activity

The AF constituents of StimulEyes benefit from an immunologic privilege, meaning the ability of the body to tolerate the introduction of antigens without eliciting an inflammatory immune response. Inflammatory immune response is when a foreign antigen is attacked by the immune system and causes rejection or other negative reactions.

The science behind StimulEyes has shown significant improvement in a wide array of conditions. The key to understanding the potential of StimulEyes as a treatment is how its various components have already demonstrated therapeutic and restorative effects on wounds, burns, pulmonary disorders, diabetic, venous and arterial ulcerations, and orthopedic cartilage improvement. The more complex ocular presentations, when used with the liquid allograft and the tissue allograft, have shown to have very desirable outcomes. The cytokines, hyaluronic acid and growth factors that form the foundational composition of StimulEyes have a demonstrated high efficacy in the treatment of other conditions and now as a possible restorative treatment for Dry Eye Disease.

StimulEyes is a prescription-level ophthalmic solution. Duly licensed providers may prescribe StimulEyes for their patients and order directly through M2 Biologics. The doctor can directly provide the solution and give comprehensive patient instructions right in the office. StimulEyes requires no stringent environmental storage requirements, can be stored at room temperature and has a shelf life of up to one year. Dosing protocols and use are at the discretion of the provider. Suggested use is one drop in each eye twice per day, ideally morning and night. However, depending on the severity of the condition, the patient may be instructed to increase the frequency of treatment. A member of the M2 Biologics Clinical Team is available to discuss dosing alternatives with the prescribing provider.

Adherence to applicable FDA regulations assures the safety of StimulEyes. Very strict FDA protocol and guidelines, as well as applicable state statutes, dictate the proper collection of AF and stipulate the stabilization, processing, sterilization and transportation of these elements by approved laboratory facilities. The processed elements then move to the final FDA and state authority regulated regenerative medicine manufacturers.

In summary: The etiology of Dry Eye Disease ranges from environmental, gland malfunction, disease, hormonal alteration and medication use. As a multifactorial disease, the solution must cover the broad spectrum of symptom relief while providing the potential for repair and restoration. Current treatment options that providers recommend range from over-the-counter eye drops and artificial teardrops on the conservative end of the treatment spectrum to surgery on the aggressive end. Outcomes are often less than desirable. Regenerative medicine opens the possibilities to treat the broad spectrum of this complex disorder. Finally, there is hope for the millions of chronic dry eye disease sufferers.