title: Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, California 94103, USA.
authors.forename: Michal T
authors.initials: MT
authors.lastname: Krauze
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.forename: Charles
authors.initials: C
authors.lastname: Noble
authors.forename: Matyas
authors.initials: M
authors.lastname: Tamas
authors.forename: John
authors.initials: J
authors.lastname: Bringas
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Krystof
authors.initials: K
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D001921:Brain; D002232:Carbocyanines / Q000493:pharmacokinetics; D002404:Catheterization / Q000295:instrumentation*; D004396:Coloring Agents / Q000493:pharmacokinetics; D018481:Convection; D016503:Drug Delivery Systems / Q000295:instrumentation*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005782:Gels; D008081:Liposomes / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012685:Sepharose; D014343:Trypan Blue / Q000493:pharmacokinetics
chemical_list: D002232:Carbocyanines; D004396:Coloring Agents; D005456:Fluorescent Dyes; D005782:Gels; D008081:Liposomes; C024286:3,3'-dioctadecylindocarbocyanine; D012685:Sepharose; D014343:Trypan Blue