Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue—cannula sealing time

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Object. Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time.

Methods. The authors used convection to deliver 4 µl of 14C-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 µl/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis.

Higher rates of infusion (1 and 5 µl/minute) caused significantly (p < 0.05) more leakback of infusate (22.7 ± 11.7% and 30.3 ± 7.8% [mean ± standard deviation], respectively) compared with lower rates (0.1 µl/minute [4 ± 3.6%] and 0.5 µl/minute [5.2 µ 3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 µl/minute (95.1 ± 2.8%) compared with higher rates (85.2 ± 4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback (35.7 ± 8.1% and 21.1 ± 7.5%, respectively) than the smaller cannula (32 gauge [5.2 ± 3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery.

Conclusions. Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.

Abstract

Object. Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time.

Methods. The authors used convection to deliver 4 µl of 14C-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 µl/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis.

Higher rates of infusion (1 and 5 µl/minute) caused significantly (p < 0.05) more leakback of infusate (22.7 ± 11.7% and 30.3 ± 7.8% [mean ± standard deviation], respectively) compared with lower rates (0.1 µl/minute [4 ± 3.6%] and 0.5 µl/minute [5.2 µ 3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 µl/minute (95.1 ± 2.8%) compared with higher rates (85.2 ± 4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback (35.7 ± 8.1% and 21.1 ± 7.5%, respectively) than the smaller cannula (32 gauge [5.2 ± 3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery.

Conclusions. Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.

Distribution of therapeutic agents within the central nervous system (CNS) by using currently available delivery techniques is problematic. Systemic delivery is limited by the blood-brain barrier, nontargeted distribution, and systemic toxicity. Diffusion-dependent methods that deliver substances by “push-pull” catheters,14 intrathecal injection,5 miniosmotic pumps,9 and drug-impregnated polymers11 can result in nontargeted distribution and a volume of distribution (Vd) that is limited by molecular weight and infusate diffusivity. An approach developed to overcome the obstacles associated with current CNS drug delivery techniques is convection-enhanced delivery.12 Previous studies have demonstrated that convection-enhanced delivery to the brain can be used to distribute small- or large-molecular-weight infusate in a homogeneous, targeted, and safe manner with a clinically effective Vd that is linearly proportional to the volume of infusion (Vi).2,7,12,13

Although previous work has demonstrated the feasibility of convective delivery in the CNS and shown that the Vi and target location (gray as opposed to white matter) influence distribution, other parameters that affect this method of substance delivery have not been determined. Critical variables that could potentially affect convective delivery include rate of infusate delivery, delivery cannula size, concentration of infusate, and preinfusion sealing time around the cannula. To determine how and whether these variables affect convective delivery, we systematically examined their effect on the Vd, percentage of recovery, and infusate leakback.

Materials and Methods

Animal Preparation

Forty female Sprague—Dawley rats, each weighing between 300 and 350 g, were used. All procedures were performed in accordance with the regulations of the Animal Care and Use Committee of the National Institute of Neurological Disorders and Stroke and the National Institutes of Health (NIH) Radiation Safety Committee.

The animals were anesthetized with intraperitoneally injected chloral hydrate (4 mg/kg) and placed in a stereotactic frame. An incision was made in the midline from the glabella to the occiput. The underlying skull was exposed and a 2-mm burr hole was placed at the cannula insertion site. The cannulae were inserted stereotactically into the right striatum 0.5 mm anterior to and 2.5 mm to the right of the bregma, and 5 mm below the dura. A variable interval between placement of the catheter and the start of the infusion, the preinfusion sealing time, allowed for adhesion of the brain tissue to the needle. After completion of the infusion, the cannula was withdrawn at a rate of 1 mm/minute. Following the procedure, the animal was killed and the brain was immediately removed and frozen in isopentane at −70°C. The rats were divided into experimental groups so that various parameters could be examined independently (Table 1).

TABLE 1

Parameters of infusion in convection-enhanced delivery to the striatum

Independent VariableNo. of RatsInfusion Volume (µl)Infusion Rate (µl/min)Concentration of Infusate (%)Cannula Size (gauge)Preinfusion Sealing Time (min)
infusion rate*440.11003270
infusion rate440.51003270
infusion rate*441.01003270
infusion rate445.01003270
cannula size440.51002870
cannula size440.51002270
sealing time440.1100320
sealing time441.0100320
infusate concentration440.5503270
infusate concentration440.5253270

This set was also used for assessing sealing time.

This set was also used for assessing cannula size and infusate concentration.

Infusion Apparatus

The hydraulic drive of the infusion apparatus consisted of a syringe pump that actuated the plunger of one of two 250-µl Hamilton syringes connected serially by polyetheretherketone tubing filled with distilled water. The second 250-µl syringe was secured to the arm of the stereotactic frame and its plunger was used to drive an abutting plunger of an infusate-filled gas-tight 10-µl Hamilton syringe. The system was noncompliant with zero dead space. Its reliability and accuracy have been previously determined.8

Infusate Material

The infusate used in all experiments was bovine serum albumin (69 kD) labeled with a 14C-methyl group (specific activity 0.024 mCi/mg). For infusion rate, cannula size, preinfusion sealing time, and full-concentration infusion experiments, the stock solution (buffered in 0.01 M sodium phosphate) was diluted (9.8:1 per volume) in 10 × phosphate-buffered saline (PBS) so that the final osmolality was 280 to 290 mOsm. The solution was further diluted with 1 × PBS for the 50% and 25% concentration experiments. Three microliters of Evan's blue dye (4.7 mg/ml of 1 × PBS) were added to every 100 µl of 14C-albumin solution so that the site of infusion could be visualized grossly within the parenchyma during animal preparation.

Tissue Analysis

The rat brains were serially sectioned at a 20-µm thickness on a cryostat (−18 to −20°C). One of every five sections was placed on salinated slides and used for histological analysis and quantitative autoradiography. Two of every five sections were placed in 20-ml scintillation vials with 5 ml of scintillation fluid and used for scintillation analysis.

The sections mounted on slides were exposed to emulsion film. Films used for specimens that had received a 100%, 50%, or 25% concentration of infusate were exposed for 4, 8, and 16 hours, respectively. The autoradiograms were then analyzed using NIH image analysis computer software. A rodbard function was used to fit the optical densities of radioactive standards with known tissue equivalents. To define the boundaries of the infusion, a threshold of approximately 15% of the maximum tissue equivalent was used. The sum of the areas was then multiplied by 0.1 mm to determine the Vd. Leakback, the portion of the infused material that flows back along the cannula tract into the white matter, was quantified by superimposing corresponding histological sections and autoradiograms. The areas of infusion located outside of the striatum in the white matter tracts and in the cannula tract were determined using NIH image analysis software. The sum of these areas was then used to determine the Vd that was outside of the striatum. This was divided by the total Vd to calculate the percentage of infusate that had leaked out of the striatum.

The percentage of recovery was determined by obtaining the counts per minute of the tissue sample using a scintillation counter. The sum of the counts per minute obtained from the tissue samples was multiplied by 2.5 (because two of every five sections were taken for analysis) to determine the total amount of radioactive infusate contained within the tissues. To estimate the total amount of radioactivity delivered, a 1-µl calibration sample was collected at the end of each infusion and the counts per minute were obtained for the sample and multiplied by 4 (because 4 µl was infused in each experiment). The percentage of recovery was calculated by dividing the total infusate radioactivity recovered in the tissue by the estimated total amount of radioactivity delivered.

Statistical Analysis

Single-factor analysis of variance (ANOVA), the Student-Newman-Keuls test, and the unpaired Student t-test were used to determine statistical significance (p < 0.05). The ANOVA and the Student-Newman-Keuls test were used with comparisons among three or more groups. The unpaired Student t-test was used in comparisons between two groups.

Sources of Supplies and Equipment

The stereotactic frame used to secure the animals was obtained from Kopf Instruments (Tujunga, CA). The syringe pump (model 22) used in the infusion apparatus was purchased from Harvard Apparatus (S. Natick, MA) and the 250-µl Hamilton syringes and the gas-tight 10-µl Hamilton syringe were purchased from Thomson Instruments (Chantilly, VA). The 14C-labeled bovine serum albumin was obtained from New England Nuclear (Boston, MA). The Hydrofluor scintillation fluid was obtained from National Diagnostics (Atlanta, GA) and the scintillation counter (model LS6000SE) from Beckman (Fullerton, CA). Biomax emulsion film was purchased from Eastman Kodak (Rochester, NY). The NIH Image 1.62 software program was developed by W. Rasband and is available from the NIH (Bethesda, MD). Statistical tests were performed using a Power Macintosh 7500/100 (Apple Computer, Cupertino, CA) with Microsoft Excel 5.0 software (Microsoft, Redmond, WA).

Results
Rate of Infusion

The Vd did not change with different infusion rates (p > 0.05), (Table 2). The Vd/Vi ratio ranged from 4.7 to 5.2 (5 ± 0.2; mean ± standard deviation). The percentage of recovery was excellent at all rates of infusion (87.6 ± 5.1%), but was highest at 0.1 µl/minute (95.1 ± 2.8%; p < 0.05). The infusate was distributed nearly exclusively in the striatum at the lower rates (0.1 and 0.5 µl/ minute), whereas at higher rates (1 and 5 µl/minute) a significant (p < 0.05) amount of infusate leakback was found in the cannula tract and the white matter overlying the striatum (Fig. 1).

TABLE 2

Summary of results

Independent VariableVd (mm3)Vd/Vi RatioInfusate Recovery (%)Infusate Leakback Into WM (%)
effect of infusion rate (µl/min)
 0.120.5 ± 4.35.1 ± 1.195.1 ± 2.84.0 ± 3.6
 0.520.8 ± 2.15.2 ± 0.586.6 ± 2.95.2 ± 3.6
 1.018.8 ± 3.84.7 ± 1.085.2 ± 4.322.7 ± 11.7
 5.019.4 ± 2.04.9 ± 0.583.7 ± 5.330.3 ± 7.8
effect of cannula size
 32 gauge20.8 ± 2.15.2 ± 0.586.6 ± 2.95.2 ± 3.6§
 28 gauge20.9 ± 2.25.2 ± 0.586.4 ± 5.035.7 ± 8.1§
 22 gauge20.3 ± 4.15.1 ± 1.082.6 ± 5.021.1 ± 7.5§
effect of concentration
 100%19.6 ± 2.74.9 ± 0.786.6 ± 2.9ANP
 50%21.5 ± 2.65.4 ± 0.684.6 ± 4.9ANP
 25%20.6 ± 1.85.1 ± 0.5NAANP
effect of preinfusion sealing time
 0.1 µl/min
  0 min20.7 ± 2.25.2 ± 0.591.1 ± 5.31.9 ± 0.5
  70 min20.5 ± 4.35.1 ± 1.195.1 ± 2.84.0 ± 3.6
 1.0 µl/min
  0 min18.6 ± 2.04.6 ± 0.587.1 ± 3.624.4 ± 15.7
  70 min18.8 ± 3.84.7 ± 1.085.2 ± 4.322.7 ± 11.7

Values are expressed as the mean ± standard deviation. Abbreviations: ANP = assessment not performed; NA = not analyzed; WM = white matter.

Significantly more recovery at 0.1 µl/minute compared with 0.5, 1, and 5 µl/minute (Student-Newman-Keuls test, p < 0.05).

Significantly more infusate leakback into the white matter than that found at infusion rates of 0.1 or 0.5 µl/minute (Student-Newman-Keuls test, p < 0.05).

All values representing infusate leakback were significantly different from the other values (Student-Newman-Keuls test, p < 0.05).

Fig. 1.
Fig. 1.

Upper and Center: Nissl-stained coronal sections obtained from the center of infused areas of rat brain with corresponding autoradiograms superimposed to show the effect of infusion rate on leakback. In a section obtained from a rat infused at 0.1 µl/minute, the infusion is contained within the striatum (upper), whereas in a section obtained from a rat infused at 5 µl/minute, there is infusion leakback out of the striatum into the overlying white matter tracts (center). Lower: Bar graph showing a comparison of the amount of leakback associated with different rates of infusion. Leakback was greater with the two higher rates of infusion (1 and 5 µl/minute) than with the two lower rates (0.1 and 0.5 µl/minute), (p < 0.05).

Cannula Size

Although the size of the cannula did not influence the Vd or the percentage of infusate recovery (Table 2), the amount of infusate leakback into the white matter and the cannula tract associated with the 32-gauge cannula (5.2 ± 3.6%) was less (p < 0.05) than that associated with the two larger cannulae (Fig. 2).

Fig. 2.
Fig. 2.

Nissl-stained coronal sections obtained from the center of infused areas of rat brain with corresponding autoradiograms superimposed to show the effect of cannula size on infusate leak-back. Upper: Section that was infused using the 22-gauge cannula. Center: Section that was infused using the 28-gauge cannula. Lower: Section that was infused using the 32-gauge cannula.

Concentration of Infusate

Differences in concentration did not alter the Vd, percentage of infusate recovery, or distribution pattern (Table 2 and Fig. 3).

Fig. 3.
Fig. 3.

Nissl-stained coronal sections obtained from the center of infused areas of rat brain with corresponding autoradiograms superimposed to show the effect of infusate concentration on Vd. Upper: Section obtained from a brain infused with 100% infusate. Center: Section obtained from a brain infused with 50% infusate. Lower: Section obtained from a brain infused with 25% infusate. The Vd was not different with the three concentrations (p > 0.05).

Preinfusion Sealing Time

Altering the preinfusion sealing time (0 minutes compared with 70 minutes) at infusion rates of 0.1 or 1 µl/minute did not affect Vd, amount of leakback, or percentage of recovery (p > 0.05), (Table 2).

Discussion

Previous work has shown that convective delivery can be used to overcome many of the obstacles associated with currently available CNS drug delivery techniques and that the Vi2 and the position of the cannula tip (in the gray or white matter)2,7,8 influence the distribution of the infusate in the brain and spinal cord.2,7,8,12 The objective of this study was to examine other variables that might affect the delivery and distribution of convection-enhanced delivery so that the parameters associated with this technique can be understood to optimize experimental and clinical application. To do this we examined the effects of the rate of infusion, cannula size, concentration of infusate, and preinfusion sealing time on convective delivery of macromolecules within the CNS.

Rate of Infusion

Variations in the infusion rate did not affect the Vd, but did alter the location of infusate distribution. At lower rates (0.1 and 0.5 µl/minute) the infusate was almost entirely contained in the target (the striatum), whereas at higher rates (1 and 5 µl/minute) there was significantly more infusate in the white matter and the cannula tract above the striatum. The umbrella-shaped region of infusate distribution in the white matter that was observed with higher rates of infusion (Fig. 1 center) represents leakback of infusate secondary to increased fluid pressure. The lower hydraulic resistance and anisotropic characteristics of the white matter tracts compared with the gray matter account for the leakback and preferential flow into the white matter pathways above the striatum.1,3,4,15

Recovery of the infusate was the highest at 0.1 µl/minute. The increased recovery at this rate compared with higher rates of infusion is explained by negligible leakback and minimal loss of infusate on the brain surface or into the ventricles via the white matter conduits of the corpus callosum.10,17,18 The results indicate that the optimum rate of infusion into gray matter of the rat brain lies between 0.1 and 0.5 µl/minute.

Cannula Size

Variations in cannula size did not influence the Vd or recovery of infusate. However, the leakback associated with the smallest cannula (32 gauge) was significantly less than those associated with the two larger cannulae (28 and 22 gauge). This may have occurred because increases in cannula diameter facilitate the formation of a low-resistance pathway that follows the surface contours of the cannula.

Leakback associated with the 22-gauge cannula was significantly smaller than that associated with the 28-gauge cannula. During tissue sectioning it was evident that the 22-gauge cannula, because of its size relative to the rat brain, caused more tissue distortion than the smaller cannulae. This distortion produced a space around the tip of the cannula, which could have acted as a sink for infusate that otherwise would have leaked back into the overlying white matter.

Concentration of Infusate

Although the results of previous experiments conducted by Kroll, et al.,6 have suggested that infusate concentration may affect the Vd associated with convective delivery, we found no difference in the Vd or recovery associated with changes in infusate concentration. This discrepancy may be due to binding, which depletes enough iron oxide particles in the lower concentration but not the higher concentration used by these researchers to create a difference in the apparent Vds.12 Another reason for the discrepancy could be that autoradiography parameters for determining the Vd can be linearly scaled to concentration changes, whereas parameters for magnetic resonance imaging of iron oxide particles and histochemical analysis have a complex relationship with different concentrations, a relationship that does not permit straightforward quantification of concentration.16 Finally, the size limitation of particles that can be distributed with convection has not been established. The extracellular matrix of the CNS may prevent distribution of iron oxide particles (20-nm diameter) by convection, and prevent credible use of these particles to examine the relationship of concentration and convective delivery.

Our findings underscore other reports that convective delivery moves infusate through the interstitium by bulk flow.2,12 This contrasts with diffusion-dependent methods, which are limited by molecular weight, infusate diffusivity, and concentration gradients for distribution.2,12

Preinfusion Sealing Time

In previous studies researchers have used preinfusion sealing times ranging from 5 to 70 minutes to enhance the retention of materials in the brain after direct injection.2,7,15 We found that preinfusion sealing time did not affect the Vd, amount of leakback, or infusate recovery at various rates of infusion (0.1 and 1 “l/minute), suggesting that elastic recoil of tissue allows for rapid sealing of the tissue surrounding the cannula.

Conclusions

The rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas variations in infusate concentration and preinfusion sealing time have no effect. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.

References

  • 1.

    Basser PJPierpaoli C: Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MR. J Magn Reson 111:2092191996J Magn Reson 111:

  • 2.

    Bobo RHLaske DWAkbasak Aet al: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:207620801994Proc Natl Acad Sci USA 91:

  • 3.

    Broaddus WCPrabhu SSGillies GTet al: Distribution and stability of antisense phosphorothioate oligonucleotides in rodent brain following direct intraparenchymal controlled-rate infusion. J Neurosurg 88:7347421998J Neurosurg 88:

  • 4.

    Geer CPGrossman SA: Interstitial fluid flow along white matter tracts: a potentially important mechanism for the dissemination of primary brain tumors. J Neurooncol 32:1932011997J Neurooncol 32:

  • 5.

    Kroin JS: Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet 22:3193261992Kroin JS: Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet 22:

  • 6.

    Kroll RAPagel MAMuldoon LLet al: Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. Neurosurgery 38:7467541996Neurosurgery 38:

  • 7.

    Lieberman DMLaske DWMorrison PFet al: Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:102110291995J Neurosurg 82:

  • 8.

    Lonser RRGogate NMorrison PFet al: Direct convective delivery of macromolecules to the spinal cord. J Neurosurg 89:6166221998J Neurosurg 89:

  • 9.

    Lum JTNguyen TFelpel LP: Drug distribution in solid tissue of the brain following chronic local perfusion utilizing implanted osmotic minipumps. J Pharmacol Methods 12:1411471984J Pharmacol Methods 12:

  • 10.

    Marmarou ANakamura TTanaka K: The kinetics of fluid movement through brain tissue. Semin Neurol 4:4394441984Semin Neurol 4:

  • 11.

    Maysinger DMorinville A: Drug delivery to the nervous system. Trends Biotechnol 15:4104181997Trends Biotechnol 15:

  • 12.

    Morrison PFLaske DWBobo Het al: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292R3051994Am J Physiol 266:

  • 13.

    Muldoon LLNilaver GKroll RAet al: Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am J Pathol 147:184018511995Am J Pathol 147:

  • 14.

    Myers RDGurley-Orkin L: New “micro push-pull” catheter system for localized perfusion of diminutive structures of the brain. Brain Res Bull 14:4774831985Brain Res Bull 14:

  • 15.

    Neuwelt EALawrence MSBlank NK: Effect of gentamicin and dexamethasone on the natural history of the rat Escherichia coli brain abscess model with histopathological correlation. Neurosurgery 15:4754831984Escherichia coli brain abscess model with histopathological correlation. Neurosurgery 15:

  • 16.

    Neuwelt EAWeissleder RNilaver Get al: Delivery of virus-sized iron oxide particles to rodent CNS neurons. Neurosurgery 34:7777841994Neurosurgery 34:

  • 17.

    Reulen HJGraham RSpatz Met al: Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. J Neurosurg 46:24351977J Neurosurg 46:

  • 18.

    Weller ROKida SZhang ET: Pathways of fluid drainage from the brain—morphological aspects and immunological significance in rat and man. Brain Pathol 2:2772841992Brain Pathol 2:

Article Information

Address reprint requests to: Edward H. Oldfield, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D37–1414, Bethesda, Maryland 20892–1414. email:oldfield@box-i.nih.gov.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Upper and Center: Nissl-stained coronal sections obtained from the center of infused areas of rat brain with corresponding autoradiograms superimposed to show the effect of infusion rate on leakback. In a section obtained from a rat infused at 0.1 µl/minute, the infusion is contained within the striatum (upper), whereas in a section obtained from a rat infused at 5 µl/minute, there is infusion leakback out of the striatum into the overlying white matter tracts (center). Lower: Bar graph showing a comparison of the amount of leakback associated with different rates of infusion. Leakback was greater with the two higher rates of infusion (1 and 5 µl/minute) than with the two lower rates (0.1 and 0.5 µl/minute), (p < 0.05).

  • View in gallery

    Nissl-stained coronal sections obtained from the center of infused areas of rat brain with corresponding autoradiograms superimposed to show the effect of cannula size on infusate leak-back. Upper: Section that was infused using the 22-gauge cannula. Center: Section that was infused using the 28-gauge cannula. Lower: Section that was infused using the 32-gauge cannula.

  • View in gallery

    Nissl-stained coronal sections obtained from the center of infused areas of rat brain with corresponding autoradiograms superimposed to show the effect of infusate concentration on Vd. Upper: Section obtained from a brain infused with 100% infusate. Center: Section obtained from a brain infused with 50% infusate. Lower: Section obtained from a brain infused with 25% infusate. The Vd was not different with the three concentrations (p > 0.05).

References

1.

Basser PJPierpaoli C: Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MR. J Magn Reson 111:2092191996J Magn Reson 111:

2.

Bobo RHLaske DWAkbasak Aet al: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:207620801994Proc Natl Acad Sci USA 91:

3.

Broaddus WCPrabhu SSGillies GTet al: Distribution and stability of antisense phosphorothioate oligonucleotides in rodent brain following direct intraparenchymal controlled-rate infusion. J Neurosurg 88:7347421998J Neurosurg 88:

4.

Geer CPGrossman SA: Interstitial fluid flow along white matter tracts: a potentially important mechanism for the dissemination of primary brain tumors. J Neurooncol 32:1932011997J Neurooncol 32:

5.

Kroin JS: Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet 22:3193261992Kroin JS: Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet 22:

6.

Kroll RAPagel MAMuldoon LLet al: Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. Neurosurgery 38:7467541996Neurosurgery 38:

7.

Lieberman DMLaske DWMorrison PFet al: Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:102110291995J Neurosurg 82:

8.

Lonser RRGogate NMorrison PFet al: Direct convective delivery of macromolecules to the spinal cord. J Neurosurg 89:6166221998J Neurosurg 89:

9.

Lum JTNguyen TFelpel LP: Drug distribution in solid tissue of the brain following chronic local perfusion utilizing implanted osmotic minipumps. J Pharmacol Methods 12:1411471984J Pharmacol Methods 12:

10.

Marmarou ANakamura TTanaka K: The kinetics of fluid movement through brain tissue. Semin Neurol 4:4394441984Semin Neurol 4:

11.

Maysinger DMorinville A: Drug delivery to the nervous system. Trends Biotechnol 15:4104181997Trends Biotechnol 15:

12.

Morrison PFLaske DWBobo Het al: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292R3051994Am J Physiol 266:

13.

Muldoon LLNilaver GKroll RAet al: Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am J Pathol 147:184018511995Am J Pathol 147:

14.

Myers RDGurley-Orkin L: New “micro push-pull” catheter system for localized perfusion of diminutive structures of the brain. Brain Res Bull 14:4774831985Brain Res Bull 14:

15.

Neuwelt EALawrence MSBlank NK: Effect of gentamicin and dexamethasone on the natural history of the rat Escherichia coli brain abscess model with histopathological correlation. Neurosurgery 15:4754831984Escherichia coli brain abscess model with histopathological correlation. Neurosurgery 15:

16.

Neuwelt EAWeissleder RNilaver Get al: Delivery of virus-sized iron oxide particles to rodent CNS neurons. Neurosurgery 34:7777841994Neurosurgery 34:

17.

Reulen HJGraham RSpatz Met al: Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. J Neurosurg 46:24351977J Neurosurg 46:

18.

Weller ROKida SZhang ET: Pathways of fluid drainage from the brain—morphological aspects and immunological significance in rat and man. Brain Pathol 2:2772841992Brain Pathol 2:

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