See the corresponding editorial in this issue pp 1126 1127 J Neurosurg 117 1128 1140 2012 Ultrasound assisted convection enhanced delivery to the brain in vivo with a novel transducer cannula assembly Laboratory investigation GEORGE 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 2 Departments 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 York Object 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 ultrasound 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 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 evalutechnique http thejns org doi abs 10 3171 2012 7 JNS11144 KEY WORDS C ONVECTION ENHANCED delivery is a novel method of drug delivery to neural tissue that bypasses the blood brain barrier 5 In CED compounds are Abbreviations used in this paper AP anteroposterior CED convection enhanced delivery CNC computer numeric controlled EBD Evans blue dye MB microbubbles MI mechanical index MOSFET metal oxide semiconductor field effect transistor OCT optimal cutting temperature TCA transducer cannula assembly UCED ultrasound assisted CED 1128 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 This article contains some figures that are displayed in color online but in black and white in the print edition J Neurosurg Volume 117 December 2012 Ultrasound assisted convection enhanced delivery interactions with the extracellular matrix and with the membranes of cells In addition some clinically important therapeutics are subject to elimination by a variety of mechanisms including clearance into capillaries biotransformation and internalization into cells Therefore the distance that an infused compound penetrates into the brain during CED is determined by the relative rates of convection and elimination In practice the infusion rate and therefore the rate of convection in the tissue are limited by the onset of associated with the infusion causes the tissue to deform sion rates the tissue deformation opens a gap between the outer surface of the catheter and the surrounding tisoutside of the catheter 9 42 Several groups have designed low higher infusion rates and enhance penetration of insuccessful designs are then tested in larger animals for Convection enhanced delivery is a promising therapy for several neural disorders perhaps most notably glioblastoma a highly malignant glioma This type of tumor characteristically has diffuse boundaries and invariably malignant cells have migrated away from the main tumor prior to resection Chemotherapy and radiation administered after resection of the tumor are unable to eliminate the remaining malignant cells in the peritumoral space As a result in 80 90 of patients the malignancy recurs within 1 3 cm of the original tumor 19 The median survival of patients with glioblastoma is approximately 1 year after diagnosis 46 Convection enhanced delivery is often used after surgery to reduce the malignant cell load in the tissue surrounding the resection cavity In this case extending the distance that infused compounds penetrate A variety of compounds have been used in animal studies of CED including small molecules5 15 36 that travel relatively far from the infusion site and larger molecules such as proteins 34 growth factors 17 nucleotides 8 liposomes and polymeric nanoparticles 43 53 which are generlarger size Some preclinical animal studies involving tumor xenografts have shown that therapeutics infused by CED can penetrate deep into the brain and produce a decrease in mortality Chemotherapeutics such as taxol 40 viral vectors encapsulated in protective liposomes 47 and recombinant chimeric proteins49 have been infused into humans in clinical trials Early Phase I II clinical trials for recurrent malignant glioma therapy 25 but Phase III plantable diffusion based polymeric drug delivery vehicles 11 The results of CED studies are highly variable and delivery of the drug to malignant cells remains a critical issue requiring additional developments 20 24 37 51 52 Therefore strategies to enhance the
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