Four things you need to know about cross-linked hyaluronic acid and corneal health

What is hyaluronic acid:

Hyaluronic Acid (HA) is found in many commercial topical tear film replacement therapies. It is a high molecular weight glycosaminoglycan that is naturally occurring in the body that helps support the wound healing process. HA has been found to have ameliorative effects in cases of keratoconjunctivitis sicca (KCS)1. HA-containing artificial tear products can recreate the viscous nature of natural tears due to its mucus-adhesive properties, while at the same time containing properties that facilitate the natural blinking process1. Ultimately, HA helps stabilize pre-corneal tear film and improves corneal hydration and lubrication. HA has also been shown to stimulate corneal epithelial cell migration and adhesion2-4. 

Related: Get our Guide to Corneal Disease

Why cross-linking matters:

The main limitation of non-cross-linked HA containing tear replacement therapies is the frequency at which owners need to apply the medication (4 to 6 times daily) in order to achieve an appropriate response to treatment. It has been found that cross-linked HA formulations have increased the amount of time HA exists on the cornea, thus leading to the same benefits that regular HA solutions provide, with the added benefit of decreased dosing frequencies5,6. Cross-linked HA has also been found to aid in the faster healing of some corneal ulcers when compared to non-cross-linked HA7-9. This added benefit of crossed-linked HA makes these types of tear film replacements superior when choosing between a product to use for patients with existing corneal damage.  

How does it work: 

Cross-linking is a chemical strategy that links HA molecules to one another, creating a polymer network. This process extends the retention properties of HA and decreases its susceptibility to enzymatic degradation, which ultimately reduces the number of times it needs to be re-applied to the cornea during the day5,6. The increased tissue scaffolding matrix that is formed secondary to cross-linking is also conducive for re-epithelialization over corneal defects7-9. There have been multiple studies performed evaluating the safety and efficacy of the use of cross-linked HA in both KCS treatment and corneal wound treatment. In one study, evaluating exaggerated dosing in rabbits for 28 days, it was concluded that cross-linked HA is very safe. The same study also evaluated the use of cross-linked HA for treatment of acute ulcer healing in dogs and cats. It was found that acute ulcers treated with cross-linked HA healed significantly faster when compared to those treated with non-cross-linked HA9. These findings provide insight that, when used appropriately, cross-linked HA can aid in the healing of certain corneal ulcers due to its properties on epithelial cell migration and adhesion. 

Clinical Application: 

Lacrimomimetics, such as HA containing ophthalmic ointments, are crucial when it comes to treating patients with KCS, as well as in patients where lagophthalmos, amongst other eyelid disorders, is present. These conditions predispose the cornea to significant ulceration, which sometimes require emergency conjunctival grafting procedures by a veterinary ophthalmologist to save the eye. Applying a tear replacement ointment to the eye throughout the day can help sustain the health of the cornea and help prevent ulcers from occurring. However, owner compliance is important for the efficacy of these medications. Cross-linked HA has shown benefits in both the healing of corneal ulcers, as well as increased owner compliance due the deceased frequency of application. This type of tear replacement therapy may be a good choice for patients suffering from tear film deficiency disorders, as well as other disorders that predispose the cornea to ulceration. 

References: 

1. Hamano T, Horimoto K, Lee M, Komemushi S. Sodium hyaluronate eye drops enhance tear film stability. Jpn J Ophthalmol. 1996; 40(1):62–65 

2. Gomes, J.A.P.; Amankwah, R.; Powell–Richards, A.; Dua, H.S. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br. J. Ophthalmol. 2004: 88: 821–825. 

3. Inoue, M.; Katakami, C. The effect of hyaluronic acid on corneal epithelial cell proliferation. Investig. Ophthalmol. Vis. Sci. 1993; 34: 2313–2315. 

4.Nishida, T.; Nakamura, M.; Mishima, H.; Otori, T. Hyaluronan stimulates corneal epithelial migration. Exp. Eye Res. 1991; 53: 753–758.  

5.Williams, D.L.; Mann, B.K. Efficacy of a crosslinked hyaluronic acid–based hydrogel as a tear film supplement: A masked controlled study. PLoS ONE. 2014; 9: 1-6. 

6.Williams, D.L.; Mann, B.K. A crosslinked HA–based hydrogel ameliorates dry eye symptoms in dogs. Int. J. Biomater. 2013; 2013. 

7.Fallacara, A.; Vertuani, S.; Panozzo, G; et. al. Novel Artificial Tears Containing Cross-Linked Hyaluronic Acid: An IN Vitro Re-Epithelialization Study. Molecules. 2017; 22: 1-13. 

8.Nishida, T.; Nakamura, M.; Mishima, H.; Otori, T. Hyaluronan stimulates corneal epithelial migration. Exp. Eye Res. 1991; 53: 753–758. 

9.Williams, D.L.; Wirostko, B.M.; Gum, G.; Mann, B.K. Topical cross–linked HA–based hydrogel accelerates closure of corneal epithelial defects and repair of stromal ulceration in companion animals. Investig. Ophthalmol. Vis. Sci. 2017; 58: 4616–4622.