Optimized cannula design and placement for convection-enhanced delivery in rat striatum

The stereotactic delivery of therapeutic agents into brain has been problematic because of reflux and leakage of the delivered agent. Good distribution of infusates by convection-enhanced delivery (CED) depends very much on cannula design, precise cannula placement and infusion rates. We have recently published cannula targeting data for the non-human primate (NHP) putamen in which we defined infusion parameters referred to as "red", "blue", and "green" zones for cannula placements that result in poor, sub-optimal and optimal volumes of distribution (Vd), respectively. Therefore, we applied our observations in NHP putamen to the rat brain. Initially, trypan blue dye was infused into agarose gels to evaluate distribution and reflux characteristics of a scaled-down cannula without step and 1-mm stepped cannula. "Stepped" means a sharp transition from a wider stent to a narrower tip; thus the distance of the cannula tip to the larger diameter attachment defines the step distance. Reflux was contained with the stepped design even with an infusion rate of 3.0 microl/min and large infusion volumes in the agarose gel study. Infusions of a recombinant growth factor, GDNF, into rat striatum demonstrated that the presence of a 1-mm stepped cannula prevented reflux and resulted in excellent distribution of GDNF in the striatum. We conclude that a stepped cannula with a 1-mm tip is important for achieving reliable distribution of infused agents in rat brain. It should be considered when local therapies such as gene transfer, local protein administration or cellular replacement are evaluated in rodent models.