Journal
BIOMATERIALS
Volume 33, Issue 35, Pages 9105-9116Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.08.060
Keywords
Depots; Scaffolds; Brain; Spinal cord; Drug delivery; Hydrogels
Funding
- Adelson Medical Research Foundation (Adelson Program in Neural Rehabilitation and Repair)
- Wings for Life
- Roman Reed Fund of California
- Nanopacific Holdings
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Biomaterial vehicles that can provide sustained, site-specific molecular delivery in the central nervous system (CNS) have potential for therapeutic and investigative applications. Here, we present in vitro and in vivo proof of principle tests of diblock copolypeptide hydrogels (DCH) to serve as depots for sustained local release of protein effector molecules. We tested two DCH, K180L20 and E180L20, previously shown to self-assemble into biocompatible, biodegradable deposits that persist four to eight weeks after injection into mouse forebrain. In vitro tests demonstrated sustained release from dialysis cassettes of the representative protein, lysozyme, dissolved in K180L20 or E180L20 hydrogels. Release time in vitro varied in relation to DCH charge and mechanical properties, and ionic strength of the media. To evaluate bioactive protein delivery in vivo, we used nerve growth factor (NGF) and measured the size of mouse forebrain cholinergic neurons, which respond to NGF with cellular hypertrophy. For in vivo tests, the storage modulus of DCH depots was tuned to just below that of CNS tissue. In comparison with NGF injected in buffer, depots of NGF dissolved in either K180L20 or E180L20 provided significantly longer delivery of NGF bioactivity, maintaining hypertrophy of local forebrain cholinergic neurons for at least 4 weeks and inducing hypertrophy a further distance away (up to 5 mm) from injection sites. These findings show that depots of DCH injected into CNS can provide sustained delivery within the blood brain barrier of a bioactive protein growth factor that exerts a predicted, quantifiable effect on local cells over a prolonged subacute time. (C) 2012 Elsevier Ltd. All rights reserved.
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