Impact of Cell Type and Density on Nerve Growth Factor Distribution and Bioactivity in 3-Dimensional Collagen Gel Cultures

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Abstract
Local delivery of protein agents is potentially important in many tissue engineering systems. In this report, we evaluate an experimental system for measuring the rate of nerve growth factor (NGF) transport and biological activity within a 3-dimensional, tissue-like environment. Fetal brain cells or PC12 cells were suspended throughout collagen gel cultures; controlled-release matrices were used to control the spatial and temporal pattern ofNGF release. Experimentallymeasured concentration profiles were compared to profiles predicted by a mathematical model encompassing diffusion and first-order elimination. Our results suggest that NGFmoves through gels by diffusion while being eliminated at a rate that depends on cell density. Since diffusion and elimination also govern protein transport in brain tissue, the collagen gel serves as a model system that replicates the main features of transport in the brain and, therefore, can be used to identify new strategies that enhance NGF distribution in the central nervous system. As an example of the utility of this biophysical model, we demonstrate that implantation of multiple controlled-release matrices can broaden NGF distribution in gel cultures; this broadening was accompanied by a significant increase in cellular biological activity. This approachmay be useful in customizingNGF distribution throughout degenerating or damaged central nervous system tissue while minimizing toxicity to surrounding healthy tissue.