Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly: Laboratory investigation

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...

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Veröffentlicht in:Journal of neurosurgery 2012-12, Vol.117 (6), p.1128-1140
Hauptverfasser: LEWIS, George K, SCHULZ, Zachary R, PANNULLO, Susan C, SOUTHARD, Teresa L, OLBRICHT, William L
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container_end_page 1140
container_issue 6
container_start_page 1128
container_title Journal of neurosurgery
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creator LEWIS, George K
SCHULZ, Zachary R
PANNULLO, Susan C
SOUTHARD, Teresa L
OLBRICHT, William L
description 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. 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. 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. 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 l
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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. 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). 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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. 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 &amp; E. 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 &lt; 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain. 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.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Catheters</subject><subject>Coloring Agents - administration &amp; dosage</subject><subject>Coloring Agents - pharmacokinetics</subject><subject>Convection</subject><subject>Drug Delivery Systems - instrumentation</subject><subject>Drug Delivery Systems - methods</subject><subject>Electric Impedance</subject><subject>Equipment Design</subject><subject>Evans Blue - administration &amp; dosage</subject><subject>Evans Blue - pharmacokinetics</subject><subject>Feasibility Studies</subject><subject>Medical sciences</subject><subject>Neurosurgery</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. 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Graft diseases</topic><topic>Tissue Distribution</topic><topic>Ultrasonics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LEWIS, George K</creatorcontrib><creatorcontrib>SCHULZ, Zachary R</creatorcontrib><creatorcontrib>PANNULLO, Susan C</creatorcontrib><creatorcontrib>SOUTHARD, Teresa L</creatorcontrib><creatorcontrib>OLBRICHT, William L</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurosurgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LEWIS, George K</au><au>SCHULZ, Zachary R</au><au>PANNULLO, Susan C</au><au>SOUTHARD, Teresa L</au><au>OLBRICHT, William L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly: Laboratory investigation</atitle><jtitle>Journal of neurosurgery</jtitle><addtitle>J Neurosurg</addtitle><date>2012-12-01</date><risdate>2012</risdate><volume>117</volume><issue>6</issue><spage>1128</spage><epage>1140</epage><pages>1128-1140</pages><issn>0022-3085</issn><eissn>1933-0693</eissn><coden>JONSAC</coden><abstract>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. 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 &amp; E. 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 &lt; 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain. 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.</abstract><cop>Charlottesville, VA</cop><pub>American Association of Neurological Surgeons</pub><pmid>22998056</pmid><doi>10.3171/2012.7.JNS11144</doi><tpages>13</tpages></addata></record>
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subjects Animals
Biological and medical sciences
Brain - metabolism
Catheters
Coloring Agents - administration & dosage
Coloring Agents - pharmacokinetics
Convection
Drug Delivery Systems - instrumentation
Drug Delivery Systems - methods
Electric Impedance
Equipment Design
Evans Blue - administration & dosage
Evans Blue - pharmacokinetics
Feasibility Studies
Medical sciences
Neurosurgery
Rats
Rats, Sprague-Dawley
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Tissue Distribution
Ultrasonics
title Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly: Laboratory investigation
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