J Neurosurg 117:1128–1140, 20121128 J Neurosurg / Volume 117 / December 2012CONVECTION-ENHANCED delivery is a novel method of drug delivery to neural tissue that bypasses the blood-brain barrier.5 In CED, compounds are into the brain parenchyma through a small hole in the skull. Material infused through the needle is carried by convection radially outward from the needle tip. Small but larger molecules and nanoparticles are hindered by Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assemblyLaboratory investigationGEORGE K. LEWIS JR., PH.D.,1 ZACHARY R. SCHULZ, M.ENG.,2 SUSAN C. PANNULLO, M.D.,3 TERESA L. SOUTHARD, D.V.M., PH.D.,4 AND WILLIAM L. OLBRICHT, PH.D.1,2Departments of 1Biomedical Engineering, 2Chemical and Biomolecular Engineering, and 4Biomedical Sciences, Cornell University, Ithaca; and 3Department of Neurological Surgery, NewYork Presbyterian Hospital–Weill Cornell Medical Hospital, New York, New YorkObject. 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 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 l/minute (Group 1), and 0.5 l/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 l/minute (Group 1) and from 0.1 to 0.5 subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultra-sound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm2. 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/cm2 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 examina-tion, 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 evalu- technique.(http://thejns.org/doi/abs/10.3171/2012.7.JNS11144)KEY WORDS Abbreviations used in this paper: AP = anteroposterior; CED = convection-enhanced delivery; CNC = computer numeric con-trolled; EBD = Evans blue dye; MB = microbubbles; MI = mechani-cal index; MOSFET = metal oxide semiconductor field-effect transistor; OCT = optimal cutting temperature; TCA = transducer cannula assembly; UCED = ultrasound-assisted CED.See the corresponding editorial in this issue, pp 1126–1127.This article contains some figures that are displayed in color on line but in black-and-white in the print edition.J Neurosurg / Volume 117 / December 2012Ultrasound-assisted convection-enhanced delivery1129interactions with the extracellular matrix and with the membranes of cells. In addition, some clinically impor-tant therapeutics are subject to elimination by a variety of mechanisms, including clearance into capillaries, bio-transformation, and internalization into cells. Therefore,
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