Mini Drug Pump for Ophthalmic Use

Purpose: To evaluate the feasibility of developing a novel mini drug pump for ophthalmic use. Methods: Using principles of microelectromechanical systems engineering, a mini drug pump was fabricated. The pumping mechanism is based on electrolysis and the pump includes a drug refill port as well as a check valve to control drug delivery. Drug pumps were tested first on the bench-top and then after implantation in rabbits. For the latter, we implanted 4 elliptical (9.9 × 7.7 × 1.8 mm) non-electrically active pumps into 4 rabbits. The procedure is similar to implantation of a glaucoma aqueous drainage device. To determine the ability to refill and also the patency of the cannula, at intervals of 4–6 weeks after implantation, we accessed the drug reservoir with a transconjunctival needle and delivered approximately as low as 1 µL of trypan blue solution (0.06%) into the anterior chamber. Animals were followed by slit lamp examination, photography, and fluorescein angiography. Results: Bench-top testing showed 2.0 µL/min delivery when using 0.4 mW of power for electrolysis. One-way valves showed reliable opening pressures of 470 mmHg. All implanted devices refilled at 4–6 weeks intervals for 4–6 months. No infection was seen. No devices extruded. No filtering bleb formed over the implant. Conclusions: A prototype ocular mini drug pump was built, implanted, and refilled. Such a platform needs more testing to determine the long term biocompatibility of an electrically-controlled implanted pump. Testing with various pharmacological agents is needed to determine its ultimate potential for ophthalmic use.

[1]  A. Manz,et al.  Micro total analysis systems. Recent developments. , 2004, Analytical chemistry.

[2]  A. Dash,et al.  Therapeutic applications of implantable drug delivery systems. , 1998, Journal of pharmacological and toxicological methods.

[3]  M. Phillip,et al.  Use of Insulin Pump Therapy in the Pediatric Age-Group , 2007, Diabetes Care.

[4]  James D. Weiland,et al.  Scalable high lead-count parylene package for retinal prostheses , 2006 .

[5]  D. Metrikin,et al.  Intravitreal drug administration with depot devices , 1994, Current opinion in ophthalmology.

[6]  R. Zare,et al.  Construction of microfluidic chips using polydimethylsiloxane for adhesive bonding. , 2005, Lab on a chip.

[7]  A. Bazarbachi,et al.  Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. , 2006, American journal of ophthalmology.

[8]  P. Sado,et al.  Ophthalmic drug delivery systems—Recent advances , 1998, Progress in Retinal and Eye Research.

[9]  Mark S Humayun,et al.  A refillable microfabricated drug delivery device for treatment of ocular diseases. , 2008, Lab on a chip.

[10]  Michael J Cima,et al.  Electronic MEMS for triggered delivery. , 2004, Advanced drug delivery reviews.

[11]  P. Hoyng,et al.  Pharmacological therapy for glaucoma: a review. , 2000, Drugs.

[12]  A. Berg,et al.  Micro Total Analysis Systems: Microfluidic Aspects, Integration Concept and Applications , 1997 .

[13]  Po-Ying Li,et al.  An electrochemical intraocular drug delivery device , 2008, 2007 IEEE 20th International Conference on Micro Electro Mechanical Systems (MEMS).

[14]  S. Shoji Micro Total Analysis Systems , 1999 .

[15]  E. Lad,et al.  Minimizing the risk of endophthalmitis following intravitreal injections. , 2006, Comprehensive ophthalmology update.

[16]  C. Kuo,et al.  Vascular endothelial growth factor: biology and therapeutic applications. , 2007, The international journal of biochemistry & cell biology.

[17]  C. R. Ethier,et al.  Ocular biomechanics and biotransport. , 2004, Annual review of biomedical engineering.

[18]  H. D. Cavanagh,et al.  In Vivo Confocal Microscopic Studies of Endothelial Wound Healing in Rabbit Cornea , 1993, Cornea.

[19]  R. Avery,et al.  Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. , 2006, Ophthalmology.

[20]  K Miyamoto,et al.  Transscleral delivery of bioactive protein to the choroid and retina. , 2000, Investigative ophthalmology & visual science.

[21]  Yasmin Sultana,et al.  Review of ocular drug delivery. , 2006, Current drug delivery.

[22]  Ming Yang,et al.  Integrated microsystems for controlled drug delivery. , 2004, Advanced drug delivery reviews.

[23]  A. Ozkiriş,et al.  Complications of intravitreal injection of triamcinolone acetonide. , 2005, Canadian journal of ophthalmology. Journal canadien d'ophtalmologie.

[24]  N. Davies,et al.  Biopharmaceutical Considerations In Topical Ocular Drug Delivery , 2000, Clinical and experimental pharmacology & physiology.

[25]  E. G. Olsen,et al.  THE HEALING OF RABBIT CORNEAL ENDOTHELIUM , 1984, Acta ophthalmologica.

[26]  D L Van Horn,et al.  Regenerative capacity of the corneal endothelium in rabbit and cat. , 1977, Investigative ophthalmology & visual science.

[27]  M. Humayun,et al.  A Passive Refillable Intraocular MEMS Drug Delivery Device , 2006, 2006 International Conference on Microtechnologies in Medicine and Biology.

[28]  D. Hinton,et al.  In vivo models of proliferative vitreoretinopathy , 2007, Nature Protocols.

[29]  T. Deckert,et al.  Evaluation of insulin pump treatment under routine conditions. , 1987, Diabetes research and clinical practice.

[30]  Shuichi Shoji,et al.  Fluids for Sensor Systems , 1998 .

[31]  A. Berg,et al.  Micro Total Analysis Systems , 1995 .

[32]  Rhea Lloyd,et al.  Food and Drug Administration approval process for ophthalmic drugs in the US , 2008, Current opinion in ophthalmology.

[33]  W. Alward,et al.  Medical management of glaucoma. , 1998, The New England journal of medicine.

[34]  E. Pels,et al.  Biocompatibility of trypan blue with human corneal cells. , 2004, Archives of ophthalmology.

[35]  Chang Sik Kim,et al.  Changes in corneal endothelial cell density and morphology after Ahmed glaucoma valve implantation during the first year of follow up , 2008, Clinical & experimental ophthalmology.

[36]  H F Edelhauser,et al.  Drug delivery for posterior segment eye disease. , 2000, Investigative ophthalmology & visual science.

[37]  K. Lim Corneal Endothelial Cell Damage from Glaucoma Drainage Device Materials , 2003, Cornea.

[38]  I. Scott,et al.  INTRAVITREAL BEVACIZUMAB (AVASTIN) FOR CENTRAL AND HEMICENTRAL RETINAL VEIN OCCLUSIONS: IBeVO Study , 2007, Retina.

[39]  J. Hsu,et al.  Drug delivery methods for posterior segment disease , 2007, Current opinion in ophthalmology.

[40]  J W Shell,et al.  Ophthalmic drug delivery systems , 1984, Survey of ophthalmology.