Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents - PubMed (original) (raw)

Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

Michal T Krauze et al. J Neurosurg. 2005 Nov.

Abstract

Object: Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials.

Methods: The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 microl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macacafascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-microl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates.

Conclusions: The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans.

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Figures

Fig. 1

Fig. 1

a: Graph depicting the flow rate (microliter per minute) of reflux for each catheter needle diameter used (18-32 gauge) in agarose gel for the delivery of trypan blue. b: Photograph illustrating the millimeter scale and catheter needles used in Fig. 1a. GA = gauge. c: A 22-gauge catheter needle allowing reflux at a 0.8-μl/minute flow rate. d: Fused silica tubing allowing reflux at a 5-μl/minute flow rate. e: The step-design cannula with fused silica tubing inside cut 1 mm from the cannula tip (12.5 × 1-mm scale, no infusion performed). f: A step-design cannula allowing a 0.5-μl/minute flow rate and 10-μl delivery volume. g: A step-design cannula permitting a 5-μl/minute flow rate and 10-μl delivery volume. h: A step-design cannula allowing a 10-μl/minute flow rate and 10-μl delivery volume. i: Step-design cannula allowing a 20-μl/minute flow rate and 10-μl delivery volume. j: Step-design cannula permitting a 50-μl/minute flow rate and 10-μl delivery volume.

Fig. 2

Fig. 2

Histological sections of rodent brain after delivery of 10 μl trypan blue at the following flow rates: 0.5 μl/minute (a), 5 μl/minute (b), 10 μl/minute (c), 20 μl/minute (d), and 50 μl/minute (e). f: Bar graph showing constant Vd from 0.5- to 10-μl/minute flow rate and decreasing Vd at 20 and 50 μl/minute (four cycles for each flow rate). g–j: Tissue damage revealed by H & E staining at the silica tip for the 0.5-, 5-, 10-, and 50-μl/minute flow rates. k: Tissue reflux after 20-μl trypan blue infusion on the 27-gauge catheter side (right) compared with no reflux seen on the step-design cannula side (left).

Fig. 3

Fig. 3

Photomicrographs of tissue sections exhibiting delivery of 10 μl DiIC18-liposomes into the rat striatum at flow rates of 0.5 μl/minute (a) and 5 μl/minute (b). c: Bar graph depicting the Vd for 10 μl DiIC18-liposomes at 0.5-μl/minute (five) and 5-μl/minute (five) flow rates. Regions generating fluorescence were delineated, and those areas were estimated by using an imaging analysis system.

Fig. 4

Fig. 4

a: Photograph illustrating the step-design cannula used in the monkey study. b: Image depicting the distribution of 100 μl trypan blue in agarose gel at a 5-μl/minute flow rate. c: Tissue section demonstrating the delivery of 700 μl rhodamine-labeled liposomes into primate corona radiata (arrows). d: Tissue section revealing delivery of 700 μl rhodamine-labeled liposomes into primate brainstem (arrows).

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