Skip to main content
SpringerLink
Log in

Controlled Release of High Molecular Weight Hyaluronic Acid from Molecularly Imprinted Hydrogel Contact Lenses

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Current dry eye treatment includes delivering comfort agents to the eye via drops, but low bioavailability and multiple administration continues to be a barrier to effective treatment. There exists a significant unmet need for devices to treat dry eye and for more comfortable contact lenses.

Methods

Using molecular imprinting strategies with an analysis of biology, we have rationally designed and synthesized hydrogel contact lenses that can release hyaluronic acid (HA) at a controlled rate.

Results

Delayed release characteristics were significantly improved through biomimetic imprinting, as multiple functional monomers provided non-covalent complexation points within nelfilcon A gels without altering structural, mechanical, or optical properties. The diffusion coefficient of 1.2 million Dalton HA was controlled by varying the number and variety of functional monomers (increasing the variety lowered the HA diffusion coefficient 1.5 times more than single functional monomers, and 1.6 times more than nelfilcon A alone).

Conclusions

HA can be delivered from a daily disposable lens at a therapeutic rate of approximately 6 μg/h for 24 h. This is the first demonstration of imprinting a large molecular weight polymer within a hydrogel and the effect of imprinting on the reptation of the long chain macromolecule from the structure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. R. Berkow, M. H. Beers, R. M. Bogin, and A. J. Fletcher. The Merck Manual of Medical Information. Merck Research Laboratories, New Jersey, 1997.

    Google Scholar 

  2. J. P. Gilbard. Human tear film electrolyte concentrations in health and dry-eye disease. Int. Ophthalmol. Clin. 34:27–36 (1994). doi:10.1097/00004397-199403410-00005.

    Article  PubMed  CAS  Google Scholar 

  3. S. K. Gupta, V. Gupta, S. Joshi, and R. Tandon. Subclinically dry eyes in urban Delhi: an impact of air pollution? Ophthalmologica. 216:368–371 (2002). doi:10.1159/000066183.

    Article  PubMed  CAS  Google Scholar 

  4. C. A. Paschides, M. Stefaniotou, J. Papageorgiou, P. Skourtis, and K. Psilas. Ocular surface and environmental changes. Acta. Ophthalmol. Scand. 76:74–77 (1998). doi:10.1034/j.1600-0420.1998.760113.x.

    Article  PubMed  CAS  Google Scholar 

  5. P. Wolkoff, J. K. Nojgaard, C. Franck, and P. Skov. The modern office environment desiccates the eyes? Indoor Air. 16:258–265 (2006). doi:10.1111/j.1600-0668.2006.00429.x.

    Article  PubMed  CAS  Google Scholar 

  6. R. I. Fox. Sjogren's syndrome. Lancet. 366:321–331 (2005). doi:10.1016/S0140-6736(05)66990-5.

    Article  PubMed  CAS  Google Scholar 

  7. M. J. Glasson, F. Stapleton, L. Keay, and M. D. P. Willcox. The effect of short term contact lens wear on the tear film and ocular surface characteristics of tolerant and intolerant wearers. Contact Lens & Anterior Eye. 29:41–47 (2006). doi:10.1016/j.clae.2005.12.006.

    Article  CAS  Google Scholar 

  8. Y. Hori, P. Argueso, S. Spurr-Michaud, and I. K. Gipson. Mucins and contact lens wear. Cornea. 25:176–181 (2006). doi:10.1097/01.ico.0000177838.38873.2f.

    Article  PubMed  Google Scholar 

  9. R. L. Chalmers, and C. G. Begley. Dryness symptoms among an unselected clinical population with and without contact lens wear. Contact Lens & Anterior Eye. 29:25–30 (2006). doi:10.1016/j.clae.2005.12.004.

    Article  Google Scholar 

  10. P. Reddy, O. Grad, and K. Rajagopalan. The Economic Burden of Dry Eye. Cornea. 23:751–761 (2004). doi:10.1097/01.ico.0000134183.47687.75.

    Article  PubMed  Google Scholar 

  11. G. Young, J. Veys, N. Pritchard, and S. Coleman. A multi-centre study of lapsed contact lens wearers. Ophthalmic Physiol. Opt. 22:516–527 (2002). doi:10.1046/j.1475-1313.2002.00066.x.

    Article  PubMed  Google Scholar 

  12. J. C. Stuart, and J. G. Linn. Dilute sodium hyaluronate (Healon) in the treatment of ocular surface disorders. Ann Ophthalmol. 17:190–192 (1985).

    PubMed  CAS  Google Scholar 

  13. P. Aragona, V. Papa, A. Micali, M. Santocono, and G. Milazzo. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br. J. Ophthalmol. 86:181–184 (2002). doi:10.1136/bjo.86.2.181.

    Article  PubMed  Google Scholar 

  14. P. Aragona, G. Di Stefano, F. Ferreri, R. Spinella, and A. Stilo. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren's syndrome patients. Br. J. Ophthalmol. 86:879–884 (2002). doi:10.1136/bjo.86.8.879.

    Article  PubMed  CAS  Google Scholar 

  15. F. Brignole, P. J. Pisella, B. Dupas, V. Baeyens, and C. Baudouin. Efficacy and safety of 0.18% sodium hyaluronate in patients with moderate dry eye syndrome and superficial keratitis. Graefe's Arch. Clin. Exp. Ophthalmol. 243:531–538 (2005). doi:10.1007/s00417-004-1040-6.

    Article  CAS  Google Scholar 

  16. T. Hamano, K. Horimoto, M. Lee, and S. Komemushi. Sodium hyaluronate eyedrops enhance tear film stability. Jpn. J. Ophthalmol. 40:62–65 (1996).

    PubMed  CAS  Google Scholar 

  17. K. Tsubota, and M. Yamada. Tear evaporation from the ocular surface. Invest. Ophthalmol. Vis. Sci. 33:2942–2950 (1992).

    PubMed  CAS  Google Scholar 

  18. N. Nakamura, M. Hikida, T. Nakano, S. Ito, T. Hamano, and S. Kinoshita. Characterization of water retentive properties of hyaluronan. Cornea. 12:433–436 (1993). doi:10.1097/00003226-199309000-00010.

    Article  PubMed  CAS  Google Scholar 

  19. G. Camillieri, C. Bucolo, S. Rossi, and F. Drago. Hyaluronan-induced stimulation of corneal wound healing is a pure pharmacological effect. J. Ocul. Pharmacol. Ther. 20:548–553 (2004). doi:10.1089/jop.2004.20.548.

    Article  PubMed  CAS  Google Scholar 

  20. J. A. P. Gomes, R. Amankwah, A. Powell-Richards, and H. S. Dua. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br. J. Ophthalmol. 88:821–825 (2004). doi:10.1136/bjo.2003.027573.

    Article  PubMed  CAS  Google Scholar 

  21. J. U. Prause. Treatment of keratoconjunctivitis sicca with Lacrisert. Scand J. Rheumatol Supple. 61:261–263 (1986).

    CAS  Google Scholar 

  22. C. Delattre, P. Michaud, J. Courtois, and M. A. Vijayalakshmi. Study of specific interactions between glucuronic acid and amino acids at the interface using pseudo bioaffinity chromatography and NMR studies. Curr. Sci. 94:1279–1284 (2008).

    CAS  Google Scholar 

  23. J. S. Park, Y. B. Lim, Y. M. Kwon, B. Jeong, Y. H. Choi, and S. W. Kim. Liposome fusion induced by pH-sensitive copolymer: Poly(4-vinylpyridine-co-N,N-diethylaminoethyl methacrylate). J. Polym. Sci. Part A: Polym. Chem. 37:2305–2309 (2000). doi:10.1002/(SICI)1099-0518(19990715)37:14<2305::AID-POLA3>3.0.CO;2-5.

    Article  Google Scholar 

  24. J. Bajorath, B. Greenfield, S. B. Munro, A. J. Day, and A. Aruffo. Identification of CD44 residues important for hyaluronan binding and delineation of the binding site. J. Biol. Chem. 273:338–343 (1998). doi:10.1074/jbc.273.1.338.

    Article  PubMed  CAS  Google Scholar 

  25. S. Willis, J. L. Court, R. P. Redman, J. Wang, S. W. Leppard, V. J. O’Byrne, S. A. Small, A. L. Lewis, S. A. Jones, and P. W. Stratford. A novel phosphorylcholine-coated contact lens for extended wear use. Biomaterials. 22:3261–3272 (2001). doi:10.1016/S0142-9612(01)00164-8.

    Article  CAS  Google Scholar 

  26. L. C. Winterton, J. M. Lally, K. B. Sentell, and L. L. Chapoy. The elution of poly (vinyl alcohol) from a contact lens: The realization of a time release moisturizing agent/artificial tear. J. Biomed. Mater Res. B: Appl. Biomater. 80B:424–432 (2006). doi:10.1002/jbm.b.30613.

    Google Scholar 

  27. J. Nichols. Contact Lens Materials: A Look at Lubricating Agents in Daily Disposables. Contact Lens Spectrum, January (2007).

  28. M. Van Beek, L. Jones, and H. Sheardown. Immobilized hyaluronic acid containing model silicone hydrogels reduce protein adsorption. J. Biomater. Sci., Polym. Ed. 12:1425–1436 (2008). doi:10.1163/156856208786140364.

    Article  Google Scholar 

  29. M. Van Beek, A. Weeks, L. Jones, and H. Sheardown. Hyaluronic acid containing hydrogels for the reduction of protein adsorption. Biomaterials. 29:780–789 (2008). doi:10.1016/j.biomaterials.2007.10.039.

    Article  PubMed  Google Scholar 

  30. M. Ali. Therapeutic Contact Lenses for Comfort Molecules. Master's Thesis, Auburn University, December 2007.

  31. M. E. Byrne, and V. Salian. Molecular Imprinting Within Hydrogels II: Progress and Analysis of the Field. Int. J. Pharm. 364:188–212 (2008). doi:10.1016/j.ijpharm.2008.09.002.

    Article  PubMed  CAS  Google Scholar 

  32. M. E. Byrne, K. Park, and N. A. Peppas. Molecular imprinting within hydrogels. Adv. Drug Del. Rev. 54:149–161 (2002). doi:10.1016/S0169-409X(01)00246-0.

    Article  CAS  Google Scholar 

  33. J. Z. Hilt, and M. E. Byrne. Configurational biomimesis in drug delivery: molecular imprinting of biologically significant molecules. Adv. Drug Del. Rev. 56:1599–1620 (2004). doi:10.1016/j.addr.2004.04.002.

    Article  CAS  Google Scholar 

  34. B. Sellergren, and C. J. Allender. Molecularly imprinted polymers: A bridge to advanced drug delivery. Adv. Drug Del. Rev. 57:1733–1741 (2005). doi:10.1016/j.addr.2005.07.010.

    Article  CAS  Google Scholar 

  35. D. Cunliffe, A. Kirby, and C. Alexander. Molecularly imprinted drug delivery systems. Adv. Drug Del. Rev. 57:1836–1853 (2005).

    CAS  Google Scholar 

  36. C. Alvarez-Lorenzo, and A. Concheiro. Molecularly imprinted polymers for drug delivery. J. Chromatogr. B. 804:231–245 (2004). doi:10.1016/j.jchromb.2003.12.032.

    Article  CAS  Google Scholar 

  37. C. J. Allender, C. Richardson, B. Woodhouse, C. M. Heard, and K. R. Brain. Pharmaceutical applications for molecularly imprinted polymers. Int. J. Pharm. 195:39–43 (2000). doi:10.1016/S0378-5173(99)00355-5.

    Article  PubMed  CAS  Google Scholar 

  38. S. Venkatesh, S. P. Sizemore, and M. E. Byrne. Biomimetic hydrogels for enhanced loading and extended release of ocular therapeutics. Biomaterials. 28:717–724 (2007). doi:10.1016/j.biomaterials.2006.09.007.

    Article  PubMed  CAS  Google Scholar 

  39. S. Venkatesh, S. P. Sizemore, J. B. Zhang, and M. E. Byrne. Therapeutic contact lenses: a biomimetic approach towards tailored ophthalmic extended delivery. Polymeric Materials: Science & Engineering (PMSE) Preprints. 94:766–767 (2006).

    CAS  Google Scholar 

  40. C. Alvarez-Lorenzo, F. Yanez, R. Barreiro-Iglesias, and A. Concheiro. Imprinted soft contact lenses as norfloxacin delivery systems. J. Controlled Release. 113:236–244 (2006). doi:10.1016/j.jconrel.2006.05.003.

    Article  CAS  Google Scholar 

  41. H. Hiratani, Y. Mizutani, and C. Alvarez-Lorenzo. Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities. Macromol. Biosci. 5:728–733 (2005). doi:10.1002/mabi.200500065.

    Article  PubMed  CAS  Google Scholar 

  42. S. Venkatesh, J. Saha, S. Pass, and M. E. Byrne. Transport and structural analysis of molecularly imprinted hydrogels for controlled drug delivery. Eur. J. Pharm. Biopharm. 69(3):852–860 (2008). doi:10.1016/j.ejpb.2008.01.036.

    Article  PubMed  CAS  Google Scholar 

  43. C. Alvarez-Lorenzo, H. Hiratani, and A. Concheiro. Contact Lenses for Drug Delivery. Am. J. Drug Del. 4:131–151 (2006). doi:10.2165/00137696-200604030-00002.

    Article  CAS  Google Scholar 

  44. M. Ali, and M. E. Byrne. Challenges and solutions in topical ocular drug-delivery systems. Exp. Rev. Clin. Pharmacol. 1:145–161 (2008). doi:10.1586/17512433.1.1.145.

    Article  CAS  Google Scholar 

  45. N. Bühler, H. P. Haerr, M. Hofmann, C. Irrgang, A. Mühlebach, B. Müller, and F. Stockinger. Nelfilcon A, a New Material for Contact Lenses. Chimia. 53:269–274 (1999).

    Google Scholar 

  46. L. Michaud, and C. J. Giasson. Overwear of contact lenses: increased severity of clinical signs as a function of protein adsorption. Optom. Vis. Sci. 79:184–192 (2002). doi:10.1097/00006324-200203000-00013.

    Article  PubMed  Google Scholar 

  47. N. J. Van Haeringen. Clinical Biochemistry of Tears. Surv. Ophthalmol. 26:84–96 (1981). doi:10.1016/0039-6257(81)90145-4.

    Article  PubMed  Google Scholar 

  48. J. Crank. The Mathematics of Diffusion. Oxford University Press, Oxford, 1975.

    Google Scholar 

  49. N. A. Peppas. Hydrogels in Medicine and Pharmacy, Volumes I & II. CRC, Boca Raton, 1987.

    Google Scholar 

  50. P. J. Flory. Principles of Polymer Chemistry. Cornell University Press, Ithaca, 1953.

    Google Scholar 

  51. P. J. Flory, and J. Rehner. Statistical mechanics of cross-linked polymer networks. I. Rubberlike elasticity. J. Chem. Phys. 11:512–520 (1943). doi:10.1063/1.1723791.

    Article  CAS  Google Scholar 

  52. P. J. Flory, and J. Rehner. Statistical mechanics of cross-linked polymer networks. II. Swelling. J. Chem. Phys. 11:521–526 (1943). doi:10.1063/1.1723792.

    Article  CAS  Google Scholar 

  53. Z. Sklubalova, and Z. Zatloukal. Systematic study of factors affecting eye drop size and dosing variability. Pharmazie. 60:917–921 (2005).

    PubMed  CAS  Google Scholar 

  54. P. G. de Gennes. Reptation of a polymer chain in the presence of fixed obstacles. J. Chem. Phys. 55:572–279 (1971). doi:10.1063/1.1675789.

    Article  Google Scholar 

Download references

Acknowledgements

We thank CIBA Vision, Inc. for funding this work and providing nefilcon macromers. We especially want to thank Dr. Lynn Winterton and Dr. John Pruitt for important discussions involving this work.

Author information

Authors and Affiliations

  1. Biomimetic & Biohybrid Materials, Biomedical Devices, and Drug Delivery Laboratories, Department of Chemical Engineering, Auburn University, Auburn, AL, 36849, USA

    Maryam Ali & Mark E. Byrne

Authors
  1. Maryam Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark E. Byrne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark E. Byrne.

Additional information

A research article submitted to Pharmaceutical Research for the Special Theme Section in Honor of NA Peppas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ali, M., Byrne, M.E. Controlled Release of High Molecular Weight Hyaluronic Acid from Molecularly Imprinted Hydrogel Contact Lenses. Pharm Res 26, 714–726 (2009). https://doi.org/10.1007/s11095-008-9818-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9818-6

KEY WORDS

Search

Navigation