Hyaluronan: A Review ofits Properties, OphthalmicUses and Research

Many scientists andengineers have dis-covered that ratherthan attempting torecreate the wheel to

develop a new tool, it is easier, and of-ten more efficient, to simply improveupon products or systems that alreadyexist. Often, nature is the inspirationfor these innovative ideas. For in-stance, nocturnal helmet geckos havebeen found to have excellent night vi-sion due to a series of distinct concen-tric zones of different refractivepowers.1,2 Studies on the gecko eyesare used to develop more effectivecameras and multifocal contact lens-es.1,2 Another example is the develop-ment of synthetic red blood cells at theUniversity of California – Santa Bar-bara in collaboration with the Univer-sity of Michigan.3,4 The synthetic redblood cells not only mimic the charac-teristics of natural red blood cells, butcan be used as carriers for therapeuticand diagnostic agents. Nature is full ofinspiring products ranging from air-plane wings inspired by birds, coolingsystems developed to mimic termitehabitats, immune systems for comput-

ers patterned after vertebrate immunesystems and healthcare products in-spired by nature.5,6 For example, artifi-cial limbs and joints are inspired bythe natural biological structures theyare intended to replace.

Similar inspirations are evident inophthalmic products. Many productsthat mimic natural biological struc-tures already exist. Some examples canbe found in the area of intraocular lensimplants (IOLs). The Crystalens(Bausch + Lomb) is an accommodatingIOL designed to mimic the natural ac-commodative ability of the crystallinelens. Similarly, and of interest in thisarticle, are the components foundthroughout the body and nature thatmimic the natural tears and can beused for treatment of dry eye and toincrease comfort and wearing timewith contact lenses.

Contact lens companies have at-tempted to mimic the ocular surface inan effort to improve comfort and wet-tability. Adding polyvinyl alcohol(PVA) and polyvinyl pyrrolidone(PVP) into contact lens materials toimprove wettability and improve com-fort are examples.7 Similarly, wetting

Dr. Rah is a staff optometristat the Massachusetts Eyeand Ear Infirmary ContactLens Service, where she specializes in medically necessary and other advanced contact lens designs.

B y M a r j o r i e R a h , O D , P h D

w w w . c l s p e c t r u m . c o m30 ■ C O N T A C T L E N S S P E C T R U M / S P E C I A L E D I T I O N 2 0 1 0

Hyaluronan, which is found throughout the body, mayhave a protective effect against oxidative damage to cells.

H Y A L U R O N A N

agents such as surfactants (for example, poloxamineand Tetronic 1304), demulcents (for example, car-boxymethylcellulose), and hyaluronan (HA) areadded to contact lens products to enhance the wetta-bility and comfort of them.7 It is the latter that is ofinterest here. HA can be found in rewetting drops,such as Aquify Long Lasting Comfort Drops (CibaVision) and Blink Contacts Lubricating Eye Drops(Abbott Medical Optics).

HA, a naturally occurring glycosaminoglycan, isfound throughout the human body — in the connec-tive tissue of the skin, inside the umbilical cord, insynovial fluid in joints and in the eye.8-10 More specif-ically with regard to the eye, it is found in the vitre-ous, lacrimal gland, cornea, conjunctiva and in tearfluid.8-12 It is thought to have anti-inflammatoryproperties and to play a role in wound healing.11-13 Inaddition, it is thought to have a protective effectagainst oxidative damage to cells because of its abilityto inhibit free radicals.13-15

Developed for ocular surgery, Healon (AbbottMedical Optics), containing 1% sodium hyaluronate,was designed as a vitreous replacement. Eventually,it was also used during cataract surgery to protect thecorneal endothelium and to provide better graft

transparency in corneal transplant surgeries.16

The random coil structure of HA results inunique water-retention properties and viscoelasticity.When used in solution in eyecare products, HA ishighly viscous, but changes in temperature, pH andshear rate lower the viscosity.8,17 These changes inshear rate are achieved with blinking. When the eyeis open, the HA is more viscous and coats the surfaceof the eye without draining, which improves the tearbreak-up time.8,14,15,18 When the eyelids blink, the vis-cosity is reduced resulting in the HA spreadingacross the eye for a smooth, lubricating blink. Thesequalities, in combination with its affinity for water,were a classic biological inspiration for producing ar-tificial tears. As a result, it was a natural progressionfor the molecule to make its way from the operatingroom to the artificial tear bottle.

Several studies have been conducted using HA inartificial tears to determine its effect on dry eye signsand symptoms (Table 1).10,19-22 These studies have in-cluded patients with mild to severe dry eye, as well aspatients with such corneal disorders as epithelialcorneal dystrophy, contact lens-induced irritation,ocular pemphigoid, filamentary keratitis and neu-rotrophic keratitis.10, 19-22 Most of the studies have

C O N T A C T L E N S S P E C T R U M / S P E C I A L E D I T I O N 2 0 1 0 ■ 31w w w . c l s p e c t r u m . c o m

AUTHORS TREATMENT RESULTS

Stuart JC, Linn JG 0.1% sodium • Patients reported relief of dry eye symptoms(1985) hyaluronate • Objective improvement in corneal stainingSand BB, Marner K, 0.1% sodium • No significant difference in Schirmer testing, tear break-up Norn MS (1989) hyaluronate, 0.2% time and rose Bengal staining, between 0.1% HA and

sodium hyaluronate, the placeboplacebo • Significant difference in objective testing between 0.2%

HA and placebo• The majority of patients preferred treatment with HA

Hamano T, Horimoto K, 0.05% sodium • No significant effect on tear break-up time noted for theLee M, Komemushi S hyaluronate vehicle or the 0.05% concentration of HA(1996) 0.1% sodium • Break-up time was significantly delayed with 0.1%

hyaluronate, 0.3% and 0.3% HA at all measurement times up to three hourssodium hyaluronate,vehicle

Johnson ME, Murphy 0.1% sodium • A significant improvement in break-up time up to six hoursPJ, Boulton M (2006) hyaluronate, 0.3% for both 0.1% and 0.3% HA, but not for saline

sodium hyaluronate, • 0.3% had greatest effect on improvement of symptoms 0.9% saline across the entire 6-hour time period of the study

Prabhasawat P, 0.18% sodium • Improvement in break-up time was significantly greater inTesavibul N, hyaluronate, 0.3% the HA group at 30 and 60 minutesKasetsuwan N (2007) hydroxypropyl-

methylcellulose/0.1% dextran

T A B L E 1

Summary of studies on the effects of hyaluronan on dry eye

focused on results from subjective questionnaires andobjective measurements of tear break-up time as theprimary outcomes, but other dry eye test results(phenol red thread test, tear meniscus height, non-invasive tear break-up time, bulbar hyperemia, fluo-rescein and lissamine green staining of the ocularsurface) have also been studied.10, 19-22 Studies show avariety of results with regard to the effect of HA inartificial tears (Table 1). As these studies were nothead-to-head trials, a comparison of results shouldnot be made, but it can be noted that these studiesdid demonstrate a positive effect of HA.

Although the literature on the topic is sparse,there are some notable contact lens studies utilizingHA. Itoi and colleagues23 evaluated the effect of HAon 3 and 9 o’clock staining in rigid gas permeablecontact lens wearers. Patients were randomized toHA or artificial tears and were followed for bothsubjective symptoms and objective clinical signs. Although no significant differences in subjectivesymptoms were found, significantly less objectivesigns (corneal staining and conjunctival hyperemia)were noted in the group using HA drops.

In addition, studies have been conducted in whichHA has been incorporated into hydrogel and siliconehydrogel lens materials to determine the effect on

protein adsorption.24, 25 The hyaluronic acid was in-corporated as a wetting agent in the soft contactlenses. Incorporating the cross-linked HA into hy-drogel lenses significantly decreased protein adsorp-tion of lysozyme, albumin and the larger proteinIgG. Similarly, incorporating cross-linked HA intosilicone hydrogel materials significantly decreasedthe uptake of lysozyme. Most recently, hydrogellenses have been designed to release HA at a con-trolled rate for therapeutic delivery of HA to the eye,to improve the wettability of contact lenses and treatthe symptoms of dry eye.26

It is evident from the products and studies men-tioned above that natural tears serve as a biologicalinspiration for HA-based ophthalmic uses. HA isfound throughout the body and can be used to mim-ic the natural tears in such products as artificial tears,contact lens rewetting agents and as a wetting agentincorporated into contact lens care products or con-tact lens materials.

These advancements in contact lens care and de-sign hopefully will lead to better comfort for ourcontact lens patients and may reduce the number ofpatients who limit wearing time or discontinue con-tact lens wear as a result of ocular dryness and dis-comfort. CLS

w w w . c l s p e c t r u m . c o m32 ■ C O N T A C T L E N S S P E C T R U M / S P E C I A L E D I T I O N 2 0 1 0

H Y A L U R O N A N

(Continued on page 45)

References1. ‘Gecko Vision’: Key To Future Multifocal Contact

Lens? Available at: sciencedaily.com/releases/2009/05/090507164407.htm

2. Roth LS, Lundström L, Kelber A, Kröger RH, UnsboP. The pupils and optical systems of gecko eyes. J Vis.2009;9:27.1-11.

3. Synthetic red blood cells developed; soft and synthetic red-blood-cell-like particles carry oxygen, drugs, and more. Availableat: newswire.ascribe.org/cgi-bin/behold.pl?ascribeid= 20091214.105409&time=13%2018%20PST&year=2009&public=0

4. Dishi N, Zahr AS, Bhaskar S, Lahann J, Mitragotri S.Red blood cell-mimicking synthetic biomaterial particles. In:Langer R, ed. Proceedings from National Academy of Sciences of theUnited States of America. 2009:21495-1499.

5. The 15 Coolest Cases of Biomimicry. Available at:brainz.org/15-coolest-cases-biomimicry/

6. Kephart JO. A biologically inspired immune system forcomputers. In: Brooks R, Maes P, eds. Artificial Life IV: Pro-ceeding of the Fourth International Workshop on the Synthesis andSimulation of Living Systems. Boston: Massachusetts Institute ofTechnology; 1994:130-139.

7. Fonn D. Targeting contact lens induced dryness and

discomfort: what properties will make lenses more comfortable.Optom Vis Sci. 2007;84:279-285.

8. Lapcik L Jr, Lapcik L, De Smedt S, Demeester J,Chabrecek P. Hyaluronan: preparation, structure, properties,and applications. Chem Rev. 1998;98:2663-2684.

9. Milas M, Rinaudo M. Characterization and properties ofhyaluronic acid (hyaluronan). In Severian D, ed. Polysaccharides:Structural Diversity and Functional Versatility. 2nd ed. NewYork, NY: Marcel Dekker;2005:535-549.

10. Stuart JC, Linn JG. Dilute sodium hyaluronate(Healon) in the treatment of ocular surface disorders. Ann Oph-thalmol. 1985;17:190-192.

11. Lerner L, Schwartz DM, Hwang DG, Howes EL,Stern R. Hyaluronan and CD44 in the human cornea and lim-bal conjunctiva. Exp Eye Res. 1998;67:481-484.

12. Yoshida K, Nitatori Y, Uchiyama Y. Localization ofglycosaminoglycans and CD44 in the human lacrimal gland.Arch Histol Cytol. 1996;59:505-513.

13. Presti D, Scott JE. Hyaluronan-mediated protective ef-fect against cell damage caused by enzymatically produced hy-droxyl (OH.) radicals is dependent on hyaluronan molecularmass. Cell Biochem Funct. 1994;12:281-288.