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A. J. Hyatt, C. Noack, K. R. Martin; Development of a Crosslinked Fibrin-Based Slow Release Delivery System for Brain-Derived Neurotrophic Factor. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4062.
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Continuous delivery of growth factors to injured and diseased neurons enhances both neuroprotection and regeneration. Damage to retinal ganglion cells can result in permanent visual loss in glaucoma and other optic nerve diseases. Sustained delivery of growth factors after injury could minimize loss of these cells. Our aim was to develop a fibrin-based delivery system to deliver brain-derived neurotrophic factor (BDNF) and other growth factors to the eye.
The carbodiimide EDC (N-[3-dimethylaminopropyl]-N-ethyl-carbodiimide hydrochloride) was used to crosslink a solution of fibrinogen. The EDC was then deactivated using 0.1 M dibasic sodium phosphate. The crosslinked gel was cut into small pieces and dried in a vacuum centrifuge. A solution of BDNF was then added to absorb into the pieces. Non-crosslinked fibrin gel containing 160 mg/mL of fibrinogen and 58 IU/mL of thrombin was mixed with the crosslinked fibrinogen pieces. BDNF release from the delivery system was quantified using Western blotting and Optiquant analysis software. The delivery system was injected through a small incision into the anterior chamber of the rat eye via an 18 gauge needle.
BDNF was released from non-crosslinked fibrin in a controlled manner for approximately 14 days in vitro. BDNF release from fibrin containing EDC crosslinked fibrinogen continued for over 28 days in vitro. Non-crosslinked fibrin degraded within 6 days in vivo whereas fibrin containing EDC crosslinked fibrinogen remained partially intact for over 3 weeks. No significant inflammation was observed during the in vivo degradation of the delivery system.
Mixing EDC crosslinked pieces of fibrinogen into fibrin gel dramatically slows the in vivo degradation of the delivery system and prolongs the release of BDNF. The delivery system is biocompatible, biodegradable, and can be injected or moulded into almost any shape to suit many different neuroprotection and neural repair applications.
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