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J. Zeroni, J. Slager, R. Hegenrother, T. Kloke, S. Varner; Sustained Delivery of Bioactive Protein With the I-Vation Intravitreal Implant. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5805.
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Demonstrate feasibility of a novel durable matrix system for sustained delivery of a bioactive protein in the rabbit eye
A model protein, Rabbit anti Goat F(ab) fragment, was used to study the activity and controlled delivery of the protein from a novel durable matrix. An ultrasonic spray method was used to mix hydrophobic polymers with the F(ab) fragment to deposit 300 ug F(ab) onto a coating on the helical I-vationTM intravitreal implant. The polymer coating used in the study consisted of a blend of durable polymers and degradable (poly)ethylene glycol (PEG)-containing polymers. All polymers used have extensive biocompatibility records. Two ultrasonic deposition techniques were utilized (Method 1 and Method 2). Once coated, the implants were implanted into the vitreous of rabbit eyes through a 25 gauge needlestick and removed at 1 and 4 weeks. Using an ELISA method, the concentration of protein and the protein activity were measured in the explanted test articles, choroid, retina, and vitreous. A parallel in vitro study was conducted in which coated coils eluted in buffer (PBS + 0.2% BSA) at 37 0C. The amount of total and active protein eluting was assayed by ELISA at regular time intervals.
Upon explantation all polymer coatings maintained mechanical integrity. No damage, cracking or delamination of the coating was observed at either time point. Of the 16 implanted animals, all remained in good health throughout the study. A significant difference in the elution profile was observed between the two formulations. In vitro elution results of Method 2 exhibited a 72% protein burst over 3 days followed by a slower sustained release. The tissue concentrations of active protein with this formulation were 9581 ng/g vitreous, 2.97 ng/mg choroid and 6.4 ng/mg retina at week 1 and 5914 ng/g vitreous, 19.04 ng/mg choroid and 8.9 ng/mg retina at week 4. In vitro results of Method 1 exhibited a zero order release profile with 90% protein activity for more than 70 days. The tissue concentrations of active protein detected with this formulation were 52.7 ng/g vitreous, 0.23 ng/mg choroid and 0.041 ng/mg retina at week 1 and 91.1 ng/g vitreous, 5.2 ng/mg choroid and 0.11 ng/mg retina at week 4.
The coating techniques utilized with the I-vationTM implant exhibit excellent in vivo mechanical properties. Implants coated with Method 1 demonstrated controlled release of active F(ab) for more than 28 days studied in vivo and more than 70 days studied in vitro. The processing technique used in Method 1 results in sustained release maintaining a high % protein activity.
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