Abstract
Dry eye is a substantial problem in a large number of human and canine patients. Numerous laboratory models for tear deficiency exist using genetically predisposed rodent models, animals treated with topical anti-muscarinics, or those kept in environments with increased air flow to produce the ocular surface changes seen in human patients. Canine keratoconjunctivitis sicca, seen in many thousands of dogs kept as companion animals, can provide a valuable spontaneous model for testing tear replacement medications that might better model disease in human patients, existing as it does in an outbred population that live in the same environments as their owners. Here the development of a crosslinked hyaluronic acid topical drop is described together with the results of trials on dogs with spontaneous keratoconjunctivitis sicca. Although hyaluronic acid in its native form in tear replacement drops shows a Newtonian rheology, the crosslinked product described here behaves in a non-Newtonian manner, with the same shear thinning shown by the tear film itself. The crosslinked product thus shows itself as a potentially valuable tear replacement medication for the human dry eye population as well as for dogs with the same condition.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Newton IS Philosophiae Naturalis Principia Mathematica. Bk 2 Sect IX, 1687, Royal Society: London.
Baieth HE . Physical parameters of blood as a non - newtonian fluid. Int J Biomed Sci 2008; 4: 323–329.
Hlavácek M . The thixotropic effect of the synovial fluid in squeeze-film lubrication of the human hip joint. Biorheology 2001; 38: 319–334.
Martin-Alarcon L, Schmidt TA . Rheological effects of macromolecular interactions in synovial fluid. Biorheology 2016; 53: 49–67.
Williams D, Middleton S, Fattahian H, Moridpour R . Comparison of hyaluronic acid-containing topical eye drops with carbomer-based topical ocular gel as a tear replacement in canine keratoconjunctivitis sicca: a prospective study in twenty five dogs. 2012 Vet Res Forum 3: 229–232.
Christensen MT, Cohen S, Rinehart J, Akers F, Pemberton B, Bloomenstein M et al. Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye. Curr Eye Res 2004; 28: 55–62.
Scaffidi RC, Korb DR . Comparison of the efficacy of two lipid emulsion eyedrops in increasing tear film lipid layer thickness. Eye Contact Lens 2007; 33: 38–44.
Moshirfar M, Pierson K, Hanamaikai K, Santiago-Caban L, Muthappan V, Passi SF . Artificial tears potpourri: a literature review. Clin Ophthalmol 2014; 8: 1419–1433.
Green-Church KB, Butovich I, Willcox M, Borchman D, Paulsen F, Barabino S et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on tear film lipids and lipid–protein interactions in health and disease. Inv Ophthalmol Vis Sci 2011; 52: 1979–1993.
Borrelli M, Schröder C, Dart JK, Collin JR, Sieg P, Cree IA et al. Long-term follow-up after submandibular gland transplantation in severe dry eyes secondary to cicatrizing conjunctivitis. Am J Ophthalmol 2010; 150: 894–904.
Rhodes M, Heinrich C, Featherstone H, Braus B, Manning S, Cripps PJ et al. Parotid duct transposition in dogs: a retrospective review of 92 eyes from 1999 to 2009. Vet Ophthalmol 2012; 15: 213–222.
Wolff E . The muco-cutaneous junction of the lid margin and the distribution of the tear fluid. Trans Ophthalmol Soc UK 1946; 66: 291.
Prydal JI, Campbell FW . Study of precorneal tear film thickness and structure by interferometry and confocal microscopy. Invest Ophthalmol Vis Sci 1992; 33: 1996–2005.
Rosenfeld L, Cerretani C, Leiske DL, Toney MF, Radke CJ, Fuller GG . Structural and rheological properties of meibomian lipid. Invest Ophthalmol Vis Sci 2013; 54: 2720–2732.
Donate A, Voigt A, Nguyen CQ . The value of animal models to study immunopathology of primary human Sjögren's syndrome symptoms. Expert Rev Clin Immunol 2014; 10: 469–481.
Yang Q, Zhang Y, Liu X, Wang N, Song Z, Wu K . A comparison of the effects of benzalkonium chloride on ocular surfaces between C57BL/6 and BALB/c mice. Int J Mol Sci 2017; 18: 509–513.
Burgalassi S, Panichi L, Chetoni P, Saettone MF, Boldrini E . Development of a simple dry eye model in the albino rabbit and evaluation of some tear substitutes. Ophthalmic Res 1999; 31: 229–235.
Meng ID, Barton ST, Mecum NE, Kurose M . Corneal sensitivity following lacrimal gland excision in the rat. Invest Ophthalmol Vis Sci 2015; 56: 3347–3354.
Aicher SA, Hermes SM, Hegarty DM . Denervation of the lacrimal gland leads to corneal hypoalgesia in a novel rat model of aqueous dry eye disease. Invest Ophthalmol Vis Sci 2015; 56: 6981.
Stern ME, Pflugfelder SC . What we have learned from animal models of dry eye?. Int Ophthalmol Clin 2017; 57: 109–118.
Kaswan RL, Salisbury MA, Ward DA . Spontaneous canine keratoconjunctivitis sicca. A useful model for human keratoconjunctivitis sicca: treatment with cyclosporine eye drops. Arch Ophthalmol 1989; 107: 1210–1216.
Williams DL . Immunopathogenesis of keratoconjunctivitis sicca in the dog. Vet Clin North Am Small Anim Pract 2008; 38 (2): 251–268.
Welburn S . One Health: the 21st century challenge. Vet Rec 2011; 168: 614–615.
Helper LC . Keratoconjunctivitis sicca in dogs. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1976; 81: 624–628.
Kaswan R, Pappas C Jr, Wall K, Hirsh SG . Survey of canine tear deficiency in veterinary practice. Adv Exp Med Biol 1998; 438: 931–939.
Williams DL . Ophthalmic disease in pedigree dogs: an ethical and welfare conundrum. AWSELVA J 2012; 16: 10–15.
Palakuru JR, Wang J, Aquavella JV . Effect of blinking on tear volume after instillation of midviscosity artificial tears. Am J Ophthalmol 2008; 146: 920–924.
Sklubalová Z, Zatloukal Z . Systematic study of factors affecting eye drop size and dosing variability. Pharmazie 2005; 60: 917–921.
Condon PI, McEwen CG, Wright M, Mackintosh G, Prescott RJ, McDonald C . Double blind, randomised, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. Br J Ophthalmol 1999; 83: 1121–1124.
Wysenbeek YS, Loya N, Sira BI, Ophir I, Ben Shaul Y . The effect of sodium hyaluronate on corneal epithelium. Invest Ophthalmol Vis Sci 1988; 29: 194–199.
Nelson JD, Farris LR . Sodium hyaluronate and polyvinyl-alcohol artificial tears preparations. A comparison in patients with keratoconjunctivitis sicca. Arch Ophthalmol 1988; 106: 484–487.
Temple-Wong MM, Ren S, Quach P, Hansen BC, Chen AC, Hasegawa A et al. Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration. Arthritis Res Ther 2016; 18: 18.
Williams DL, Mann BK . A crosslinked HA-based hydrogel ameliorates dry eye symptoms in dogs. Int J Biomater 2013; 2013: 460437.
Williams DL, Mann BK . Efficacy of a crosslinked hyaluronic acid-based hydrogel as a tear film supplement: a masked controlled study. PLoS ONE 2014; 9: e99766.
Williams DL, Wirostko BM, Gum G, Mann BK . Topical cross-linked HA-based hydrogel accelerates closure of corneal epithelial defects and repair of stromal ulceration in companion animals. Invest Ophthalmol Vis Sci 2017; 58: 4616–4622.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no conflict of interest.
Rights and permissions
About this article
Cite this article
Williams, D. Optimising tear replacement rheology in canine keratoconjunctivitis sicca. Eye 32, 195–199 (2018). https://doi.org/10.1038/eye.2017.272
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/eye.2017.272
This article is cited by
-
A liposomal formulation of cyclosporine a shows promising results in treating symptoms of moderate to severe dry eye disease in dogs
Drug Delivery and Translational Research (2026)