TearLab Osmolarity – a New Gold Standard, VALIDATED!

In a few short years since its commercial introduction in mid-2009, published dry eye research utilizing the TearLab Osmolarity System has included over 1,100 study subjects, with many additional studies currently in review awaiting publication. By comparison, the compendium of clinical tear osmolarity data spanning 26 years between 1978 and 2004 has comprised just over 1,400 individuals.

Moreover, to validate the accuracy, repeatability, variability and clinical utility of the TearLab for its FDA 510(k) clearance, over six thousand data points were collected over four clinical trials and thirteen analytical trials, a summary of which can be found at: http://www.accessdata.fda.gov/cdrh_docs/pdf8/K083184.pdf.

This, in addition to the hundreds of thousands of tests that have already been performed around the world for the clinical diagnosis, severity assessment and management of dry eye disease (without a single adverse event), makes the TearLab Osmolarity System one of the most utilized and validated in vitro diagnostic devices in ophthalmic history.

Tear fluid osmolarity has long been reported as the single best marker for the diagnosis and management of dry eye disease. A disease which, by definition, limits the specimen available for analysis. It has been reported that severe dry eye patients maintain less than 200 nanoliters (nL) of tear fluid within the marginal tear strip. Due to this constraint, vanishingly small samples must be analyzed instantaneously upon collection in order to minimize errors arising from evaporation during sample transfer and handling. As a result, the TearLab Osmolarity System incorporates a lab-on-a-chip technology which simultaneously collects and measures a 50-nanoliter tear sample – a volume approximately the size of the period at the end of this sentence.

The TearLab uses capillary action to pull tears directly from the inferior lateral meniscus. From there it is a relatively straightforward process, as the TearLab rapidly converts the temperature compensated electrical impedance into the patient’s osmolarity in mOsms/L in less than 10 seconds. The final osmolarity values is proportional to both the ionic charge of the sample and the geometry of the capillary, which is built from a 75 micron-deep sigmoidal microfluidic channel to promote both collection and repeatable introduction of electric fields into the sample. Furthermore, because the microfluidic dynamics within the capillary is a metastable environment due to the constant evaporative flux and surface tension driven flow, data from the lab-on-a-chip is continuously fed to an on-board processor, thousands times per second, in order to execute dynamic compensation. Analysis of the electrical impedance is also highly temperature dependent, which requires sensitive and continuous compensation in order to achieve the high-resolution osmolarity measurement that the TearLab ultimately provides. See, simple!

As one of the first lab-on-a-chip, nanofluidic analyzers to reach the market for widespread use, the TearLab has elicited significant interest in both the clinical and scientific community. Therefore, we felt it important that this technology be well validated and vetted prior to commercial introduction.

To accomplish this goal, TearLab launched a series of studies to demonstrate substantial equivalence to traditional laboratory vapor pressure osmometers traceable to national standards, to establish usability in the hands of intended users (non-laboratory trained healthcare professionals), to validate the measurement of TearLab osmolarity against clinically accepted dry eye standards of analysis, and finally to validate that TearLab is meeting its post-market objectives of providing a quantitative and objective tool to manage dry eye patients.  Over a period of three years, over 6,500 TearLab tests, in over ten countries were conducted to perform these studies and validate this technology, including:

FDA 510(k) Studies (2,500+ tests)

1. TearLab Calibration – Human Tears
2. TearLab Matrix Effects & Interfering Substances
3. Internal Precision – Within Run & Day to Day
4. Internal Precision – Between Instrument
5. Internal Precision – Lot to Lot
6. Linearty
7. Internal Method Comparison
8. Limits of Detection
9. External Precision – Within Run & Day to Day

External Method Comparison

• Clinical Laboratory Improvement Act (CLIA) Studies  (1,000+ tests)
• Core Validation Studies (2,000+ tests)
• Consumer Preference Study  (1,000+ tests)

In addition, TearLab has been embraced by the scientific and research community presenting TearLab dry eye data at scientific meetings annually since its market introduction, including:

• European Society Cataract and Refractive Surgery (ESCRS) 2009
• American Academy of Ophthalmology (AAO) – Corneal Society 2009
• American Academy of Optometry (AAOpt)  2009
• Association for Research in Vision and Ophthalmology (ARVO)  2009
• British Contact Lens Association (BCLA) 2009
• American Society Cataract and Refractive Surgery (ASCRS) 2009
• SECO 2009
• American Ophthalmology Society (AOS)  2010
• Association for Research in Vision and Ophthalmology (ARVO) 2010
• European Society Cataract and Refractive Surgery (ESCRS) 2010
• American Association of Clinical Chemistry (AACC) 2010
• Tear Film Ocular Surface Society (TFOS) 2010
• British Contact Lens Association (BCLA) 2010
• American Society Cataract and Refractive Surgery (ASCRS) 2010
• American Academy of Ophthalmology (AAO)  2010
• VisionExpo 2010
• American Academy of Optometry (AAOpt)  2010
• Hawaiian Eye 2011

Finally, in a very short period of time, the TearLab test has been vetted in a long list of well-respected publications, including:

1. Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6125-30. Epub 2010 Jul 14. (http://www.ncbi.nlm.nih.gov/pubmed/20631232)

1. J. Bron, N. Yokoi, E. A. Gaffney and J. M. Tiffany. A Hyperosmolar Gradient in the Tear Meniscus: A Hypothesis to Explain Pathophysiological Events at the Lid Margin. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 5199. (http://abstracts.iovs.org/cgi/content/abstract/51/5/5199)

1. Tomlinson A, McCann LC, Pearce EI. Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques. Cornea. 2010 Sep;29(9):1036-41. (http://www.ncbi.nlm.nih.gov/pubmed/20577088)

1. B. D. Sullivan, D. C. Eldridge, M. Berg, V. Kosheleff, A. Porreco, J. Truitt and M. A. Lemp. Diagnostic Performance of Osmolarity Combined With Subset Markers of Dry Eye Disease in an Unstratified Patient Population. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 3380. (http://abstracts.iovs.org/cgi/content/abstract/51/5/3380)

1. P. Versura, V. Profazio, C. Coslovi, M. Fresina and E. C. Campos. Hyperosmolar Stress is Related to HLA-DR Overexpression in Non Sjogren’s Dry Eye Patients and in Cultured Human Conjunctival Epithelial Cells. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 1917. (http://abstracts.iovs.org/cgi/content/abstract/51/5/1917)

1. A. Keech, M. Senchyna, B. D. Sullivan, M. A. Lemp, L. W. Jones and M. J. Brubaker. Impact of Time Between Collection on Human Tear Film Fluid Osmolarity. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 4174. (http://abstracts.iovs.org/cgi/content/abstract/51/5/4174)

1. D. C. Eldridge, B. D. Sullivan, M. D. Berg, M. A. Lemp and D. S. Durrie. Longitudinal Variability of Tear Film Osmolarity in Normal and Dry Eye Patients. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 3379. (http://abstracts.iovs.org/cgi/content/abstract/51/5/3379)

1. Lemp MA. Management of dry eye disease. Am J Manag Care. 2008 Apr;14(3 Suppl):S88-101. (http://www.ncbi.nlm.nih.gov/pubmed/18452372)

1. Larmo PS, Järvinen RL, Setälä NL, Yang B, Viitanen MH, Engblom JR, Tahvonen RL, Kallio HP. Oral sea buckthorn oil attenuates tear film osmolarity and symptoms in individuals with dry eye. J Nutr. 2010 Aug;140(8):1462-8. Epub 2010 Jun 16. (http://www.ncbi.nlm.nih.gov/pubmed/20554904)

10. Fortes MB, Diment BC, Di Felice U, Gunn AE, Kendall JL, Esmaeelpour M, Walsh NP. Tear Fluid Osmolarity as a Potential Marker of Hydration Status. Med Sci Sports Exerc. 2011 Jan 12. (http://www.ncbi.nlm.nih.gov/pubmed/21233774)

11. Versura P, Profazio V, Campos EC. Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases. Curr Eye Res. 2010 Jul;35(7):553-64. (http://www.ncbi.nlm.nih.gov/pubmed/20597641)

12. C. Jacobi, F. E. Kruse and C. Cursiefen. Tear Film Omolarity in Dry-Eye Disease. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 3381. (http://abstracts.iovs.org/cgi/content/abstract/51/5/3381)

13. M. Schargus, F. Wolf, B. Sullivan, M. Feuchtenberger and G. Geerling. Tear Film Osmolarity and Dry Eye Severity Index in Patients with Rheumatoid Arthritis or Sjögren Syndrome. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 6250. (http://abstracts.iovs.org/cgi/content/abstract/51/5/6250)

14. Benelli U, Nardi M, Posarelli C, Albert TG. Tear osmolarity measurement using the TearLab Osmolarity System in the assessment of dry eye treatment effectiveness. Cont Lens Anterior Eye. 2010 Apr;33(2):61-7. Epub 2010 Feb 12. (http://www.ncbi.nlm.nih.gov/pubmed/20153684)

15. P. G. Dentone, S. P. Epstein, G. S. Raynor and P. A. Asbell. Tear Osmolarity–Comparison and Repeatibility of Freezing Point and Electrical Impedance With Small Volumes. Invest Ophthalmol Vis Sci 2010;51: E-Abstract 4189. (http://abstracts.iovs.org/cgi/content/abstract/51/5/4189)

16. Selected Tear Film Ocular Surface Society (TFOS) 2010 Papers: (http://www.tearfilm.org/pdfs/TFOS_Abstracts.pdf)

• Keynote Address: EFFECTS OF TOPICAL DRUG PRESERVATIVES ON THE TEAR FILM AND OCULAR SURFACE. Christophe Baudouin, Quinze-Vingts National Ophthalmology Hospital, Vision Institute, University Paris 6, Paris, France

• MODIFICATION OF THE TEAR FILM OSMOLARITYWITH THE USE OF CONTACT LENSES IN OMAFILCONA AND METHAFILCONA MATERIALS. Montani Giancarlo, University Of Salento Formazione Continua In Medicina, Lecce, Italy

• EVALUATION OF TEAR OSMOLARITY IN PATIENTS UNDERGOING PHACOEMULSIFICATION CATARACT SURGERY.Arturo E. Grau (MD), Maria C. Morales (PhD), Juan A. Durán (MD, PhD). Instituto Clínico-Quirúrgico de Oftalmología, Bilbao, Vizcaya, Spain

• LACK OF CORRELATION OF COMMONLY USED TESTS FOR THE ASSESSMENT OF SEVERITY OF DRY EYE DISEASE. Benjamin D. Sullivan, Anthony J. Bron, Christophe Baudouin, Gary N. Foulks, Kelly K. Nichols, Alan Tomlinson, Michael S. Berg, Michael A. Lemp.

Osmolarity was proposed as a potential “gold standard” for dry eye disease by the Dry Eye Workshop (DEWS) Report, in 2007 (http://www.tearfilm.org/dewsreport/pdfs/TOS-0502-DEWS-noAds.pdf)

“In the past, although the measurement of tear osmolarity has been offered as a “gold standard” in dry eye diagnosis, its general utility as a test has been hindered by the need for expert technical support; thus, its use has been confined to a small number of specialized laboratories. The feasibility of this objective test is greatly enhanced by the imminent availability of a commercial device that will make the technology generally available.”

It now appears with the successful introduction of the TearLab Osmolarity System, the goal of a practical gold standard device has been achieved.