MANAGING CLD

Platelet-Rich Plasma in the Treatment of Contact Lens Discomfort

A therapy first used in cardiac surgery is showing promise in relieving symptoms of ocular discomfort.

By Edward S. Jarka, OD, MS

In the United States, approximately 3 million lens wearers discontinue wear each year because of contact lens discomfort (CLD) (Fonn, 2007). This has an economic impact on both the industry and on individual practitioners (Rumpakis, 2010; Nichols J, 2013).

The Tear Film and Ocular Surface Society’s (TFOS) International Workshop on Contact Lens Discomfort (CLDW) defined CLD as “a condition characterized by episodic or persistent adverse ocular sensations related to lens wear, either with or without visual disturbance, resulting from reduced compatibility between the contact lens and the ocular environment, which can lead to decreased wearing time and discontinuation of contact lens wear,” (Nichols K et al, 2013).

This definition does not apply to individuals who had dry eye before starting contact lens wear. However, as with dry eye, the causes and the lack of correlation between clinical signs and symptoms can make the management of CLD a significant clinical problem.

Changing lens material, care systems, and lens replacement schedules, as well as using additional wetting agents, are well known management techniques for CLD, but the success of any one technique is unpredictable at best. The CLDW describes potential management techniques, including neuromodulation of the discomfort sensation by means of pharmaceuticals and the use of autologous serum (AS) (Papas et al, 2013).

Over the last six years, my colleagues—Mark Kahrhoff, OD, and John Crane, OD—and I have investigated the use of platelet-rich plasma (PRP) in a number of ocular surface conditions including CLD. This article will review the biology behind PRP, how PRP is different from AS, and the experiences of subjects treated with PRP related to contact lens wear. It will also review future research projects involving the use of PRP in CLD and other ocular surface diseases.

Platelet Biology

Before understanding the differences between PRP and AS, it is important to understand the value that platelets have in healing the ocular surface. Activated platelets release a number of biologically active components that contribute to wound repair in all types of tissues, including the tissues of the ocular surface.

Platelets are the smallest blood component, measuring about two microns. This is notably smaller than red blood cells, which measure six microns. Platelets are fragments derived from megakaryocytes in the bone marrow, and like red blood cells, they lack a nucleus. Platelets contain two types of granules: 1) dense granules that contain calcium, adenosine diphosphate, adenosine triphosphate, thromboxane, and serotonin; and 2) alpha granules that release a much larger number of biologically active proteins compared to the dense granules (Table 1). Platelets circulate in the blood at high concentrations ranging from 150,000/L to 400,000/L for the purpose of vascular repair throughout the body (Greer, 2008).

Platelets exist in two morphologic forms: an inactive, smooth-surfaced form and an activated, highly multi-pseudopodial form (Imanishi et al, 2000; Everts, 2007). Upon activation, the platelets release the contents within the dense and alpha granules, which induces their various cellular effects including DNA synthesis, production of extra-cellular matrix molecules, cell proliferation, and cell migration (Figure 1).

Figure 1. A platelet begins as a smooth-surfaced blood component. When activated, it becomes multi-pseudopodial and releases the following growth factors: EGF = Epithelial Growth Factor; KGF = Keratinocyte Growth Factor; FGF = Fibroblast Growth Factor; TGF = Transforming Growth Factor; PDGF = Platelet Derived Growth Factor. Each factor can influence proliferation and/or migration in the layers of the cornea. The red arrows indicate interaction known to occur between the growth factors. Adapted from Imanishi et al (2000) and Everts (2007).

Platelet-Rich Plasma in Tissue Repair

Autologous platelet-enriched concentrates were first used in 1987 in cardiac surgery (Ferrari et al, 1987). Since then, PRP has been successfully used in various specialties such as maxillofacial, cosmetic, spine, orthopedic, and podiatric as well as for general wound healing (Gamradt et al, 2007; Everts et al, 2006). Recently, PRP has been investigated in the use of ophthalmic conditions including dry eye (Alio et al, 2007), chemical burns (Panda et al, 2012), and post-laser-assisted in situ keratomileusis (LASIK) dry eye syndrome (Alio et al, 2007) as well as in patients who discontinued contact lens wear because of discomfort (Jarka et al, 2012).

Platelet-Rich Plasma Versus Autologous Serum

AS is the clear liquid that results after the centrifugation of blood. It contains components similar to natural tears, but does not contain the formed elements of the blood (red blood cells, white blood cells, or platelets), nor the clotting proteins. Fox et al (1984) first described the use of AS; since then, AS has been useful in the treatment of neurotrophic ulcers, superior limbic keratitis, persistent epithelial defects, graft-versus-host disease, and various dry eye conditions (Matsumoto et al, 2004; Goto et al, 2001; Tsubota et al, 1999; Ogawa et al, 2003; and others. Full list available at www.clspectrum.com/references.). AS preparation is very labor intensive, taking hours to prepare after the venipuncture.

Different forms of platelet-enriched preparations have been described in the literature. PRP involves a double centrifugation process that enriches a portion of the plasma fraction of a patient’s blood to a platelet concentration above baseline. The platelets in PRP are then activated when used for its respective clinical purpose (Marx, 2001).

Another platelet preparation called Plasma Rich in Growth Factors or “Preparation Rich in Growth Factors” (PRGF) is comprised of 100% autologous and biocompatible products elaborated using a one-step centrifugation process (Anitua, 2001; Anitua et al, 2007). Eye-Platelet-Rich Plasma (E-PRP) is a hybrid of both PRP and PRGF that can be prepared as a gel or as a topical solution (Alio et al, 2012).

We will refer to our preparation as PRP, although our uses are primarily in the form of topical solution. Regardless of the acronym used, autologous PRP provides a greater concentration of essential growth factors and cell adhesion molecules through the concentration of platelets in a small volume of plasma.

The higher concentration of growth factors and cell adhesion molecules in PRP plays a major role in wound healing and enhances the healing process at the site of the ocular surface compromise (Alio, Abad et al, 2007). PRP has been successful in treating dormant corneal ulcers, moderate-to-severe dry eye syndrome, and dry eye post-LASIK (Alio, Abad et al, 2007; Alio, Colecha et al, 2007; Alio, Pastor et al, 2007).

PRP can be prepared point-of-care, taking no more than 30 minutes after venipuncture with the use of specialized platelet concentrating kits and centrifuges (Figure 2). I have used 30% to 100% concentrations of PRP for a variety of ophthalmic disorders, but we recently began studying the effects of PRP on more mild ocular surface conditions including CLD.

Figure 2. Platelet-rich plasma preparation with the Harvest SmartPReP System. The Harvest SmartPReP A) Centrifuge; B) 120-Kit that provides two PRP preparations; C) Result of preparation showing 1) platelet-poor plasma; 2) buffy coat containing platelets, and 3) red blood cells.

PRP and Its Effect on the Physical Changes Observed in Lens Wear

Morphological Changes in the Corneal Epithelia Corneal epithelial thinning and increased cell size have been observed after contact lens wear (Robertson, 2013; Ladage, 2004; Bergmanson, 2001). It has been proposed that the increase in cell size is associated with slowing of epithelial renewal (Robertson, 2013) as well as other factors such as mechanical compression (Bergmanson, 2001; Lemp and Gold, 1986).

PRP provides two growth factors that are released from platelets after activation: epithelial growth factor (EGF) and transforming growth factor beta (TGF-β). Both EGF and TGF-β improve corneal epithelia renewal by 1) enhancing DNA synthesis, 2) increasing production of extra-cellular matrix molecules, and 3) increasing cellular proliferation. In addition, certain concentrations of TGF-β have been found to enhance the growth-promoting effects of EGF (Carpenter and Cohen, 1979; Nishida et al, 1984; Jorissen et al, 2003; Roberts, 2002; and others).

Although there is no direct connection between CLD and morphological changes in the cornea (Efron et al, 2013), my colleagues and I have found that 30% PRP dosed twice a day in contact lens wearers improves contact lens comfort in former and current lens wearers after other attempts to improve CLD have failed (Jarka et al, 2012).

Morphological Changes in Stroma Although no studies have shown an association between a decrease in keratocyte density and CLD (Efron et al, 2013), several studies have demonstrated a loss of keratocyte density in the anterior and posterior stroma after wearing various contact lens types (Efron et al, 2002; Jalbert and Stapleton, 1999; Weed et al, 2007).

Moreover, a number of growth factors released from activated platelets have a beneficial effect in corneal epithelial and stromal morphology. Platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and TGF have effects in both the proliferation and migration of keratinocytes (Saghizadeh et al, 2001; Jester et al, 2002; Wilson et al, 1999).

Patients who have significant corneal erosions with a history of contact lens wear have stabilized after about three months of treatment with 30% to 50% PRP concentrates. Studies at the University of Missouri-St. Louis are planned to evaluate keratinocyte density in contact lens wearers with and without PRP treatment.

Other Ocular Surface Changes Associated with Contact Lens Wear Goblet cell density, bulbar conjunctival redness, and limbal redness are some other observed morphological changes that occur with contact lens wear. However, although the aforementioned changes to the ocular surface are observed with contact lens wear, there is little evidence that these changes are associated with CLD (Efron et al, 2013).

In a study recently completed at the University of Missouri-St. Louis, contact lens wearers who complained of discomfort showed a decrease in both limbal and bulbar conjunctival redness, as well as improved contact lens comfort, when treated with PRP compared to masked placebo controls. Other studies have reported improvement in these same ocular surface parameters in other ocular surface diseases including dry eye (Alio, Colecha et al, 2007), chemical burns (Panda et al, 2012), and post-LASIK dry eye syndrome (Alio, Pastor et al, 2007).

Current and Future Studies

The benefits of PRP for patients experiencing reduced contact lens wearing time or CLD are clear, but a well-defined protocol and dosing regimen is still required. There is far more literature and experience in using autologous PRP for more advanced ocular surface diseases. In my experience and that of others who have used PRP, a 50% to 60% PRP concentrate improves the comfort and visual performance in Sjögren’s syndrome patients to a greater degree compared to other available treatments, including AS.

The use of autologous PRP in less severe cases of ocular surface diseases is controversial, but if we think of contact lens wear as a chronic iatrogenic disease, then using a point-of-care treatment that has the potential to revitalize the ocular surface becomes a viable and cost-effective option to maintain both lens wear and an ocular surface in a state of healthy homeostasis.

My colleagues and I recently identified a compound that results in enhanced platelet activation and a longer retention time of the growth factors on the ocular surface; this may make this therapeutic option more predictable. Early laboratory evaluations indicate that we can expect improvement in the ocular surface faster and less expensively with this enhanced PRP protocol compared to with amniotic membranes.

Another area of research interest is the use of PRP in patients who have meibomian gland dysfunction (MGD). It has been reported that sebaceous glands (Takikawa et al, 2011) and the lacrimal gland (Avila et al, 2014) can demonstrate improved function when exposed to PRP concentrates. Clinically, patients who have dry eye due to multiple contributing factors experienced improvement in their signs of MGD, including telangiectasia and meibomian gland orifice capping, after receiving 30% PRP concentrate dosed twice a day over a five-month period. It is difficult to say what contributed to the patients’ clinical improvement, so controlled studies in subjects who have notable meibomian gland dropout are planned.

Finally, patients who have a diagnosis of rosacea with reduced contact lens wearing ability have also experienced a clinical benefit from the use of PRP. Because PRP has a bacteriostatic ability against Staphylococcus aureus and Staphylococcus epidermidis, it is likely that it could have an effect on the primary cause of rosacea—Demodex folliculorum—by either direct anti-parasitic activity or by improving the secretions from the sebaceous glands. Either way, the difficulty will be in the preparation, dosing, and retention of the PRP to the ocular surface as well as the periocular area.

At the University of Missouri-St. Louis, the use of PRP for CLD is an exciting and evolving area of research that shows clinical promise. The primary goal of the research is to improve the comfort and vision of patients suffering from ocular surface disease by adapting regenerative medicine techniques for use on the ocular surface, whether the primary cause is due to lens wear or to other contributing factors. CLS

Dr. Jarka would like to thank his colleagues Dr. Mark Kahrhoff and Dr. John Crane of Complete Vision Care for their invaluable participation in developing the techniques and applications described in this article.

For references, please visit www.clspectrum.com/references and click on document #236.

Dr. Jarka is an associate clinical professor at the University of Missouri-St. Louis College of Optometry. His research interests are regenerative medicine applications in ocular surface disease.