title: Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly: laboratory investigation.
abstract: OBJECTIVE
  In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system.
  
  
  METHODS
  Forty Sprague-Dawley rats (350-450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm(2). An additional 4 Sprague-Dawley rats (350-450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm(2) for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E.
  
  
  RESULTS
  The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain.
  
  
  CONCLUSIONS
  The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA. george@cornellbme.com
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Schulz
authors.forename: Susan C
authors.initials: SC
authors.lastname: Pannullo
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Southard
authors.forename: William L
authors.initials: WL
authors.lastname: Olbricht
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D057785:Catheters; D004396:Coloring Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018481:Convection; D016503:Drug Delivery Systems / Q000295:instrumentation* / Q000379:methods; D017097:Electric Impedance; D004867:Equipment Design; D005070:Evans Blue / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005240:Feasibility Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014465:Ultrasonics
chemical_list: D004396:Coloring Agents; D005070:Evans Blue