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George K. Lewis Jr., Zachary R. Schulz, Susan C. Pannullo, Teresa L. Southard and William L. Olbricht

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 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/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 evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.

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Andrew Post, T. Blaine Hoshizaki, Michael D. Gilchrist, Susan Brien, Michael D. Cusimano and Shawn Marshall

Object

The purpose of this study was to examine how the dynamic response and brain deformation of the head and brain—representing a series of injury reconstructions of which subdural hematoma (SDH) was the outcome—influence the location of the lesion in the lobes of the brain.

Methods

Sixteen cases of falls in which SDH was the outcome were reconstructed using a monorail drop rig and Hybrid III headform. The location of the SDH in 1 of the 4 lobes of the brain (frontal, parietal, temporal, and occipital) was confirmed by CT/MR scan examined by a neurosurgeon.

Results

The results indicated that there were minimal differences between locations of the SDH for linear acceleration. The peak resultant rotational acceleration and x-axis component were larger for the parietal lobe than for other lobes. There were also some differences between the parietal lobe and the other lobes in the z-axis component. Maximum principal strain, von Mises stress, shear strain, and product of strain and strain rate all had differences in magnitude depending on the lobe in which SDH was present. The parietal lobe consistently had the largest-magnitude response, followed by the frontal lobe and the occipital lobe.

Conclusions

The results indicated that there are differences in magnitude for rotational acceleration and brain deformation metrics that may identify the location of SDH in the brain.