Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation
Abstract
:1. Introduction
2. Results
2.1. High-Frequency Electroporation BBBD Analysis
2.1.1. Temporal BBBD Characterization
2.1.2. BBBD with Varied V/d and Burst Number
2.2. Numerical BBBD Analysis
2.3. Histomorphologic Analyses
2.4. Secondary Electrical, Thermal, and Accelerometry Measurements
2.4.1. Electrical Impedance Spectroscopy for Monitoring Changes in Tissue Impedance
2.4.2. Fiber Optic Temperature Sensing for Monitoring Joule Heating Effects
2.4.3. Accelerometry Measurements for Muscle Excitation
3. Discussion
4. Materials and Methods
4.1. Assurances and Surgical Procedures
4.2. High-Frequency Electroporation and Parameter Selection
4.3. Magnetic Resonance Imaging and Gd-EBD BBB Disruption Volumetrics
4.4. Histomorphologic Analyses of Gd-EBD Treated Rodents
4.5. Quantification of Evans Blue Dye
4.6. Numerical Determination of BBBD Temporal Thresholds
4.7. Secondary Electrical, Thermal, and Accelerometry Measurements
4.7.1. Electrical Impedance Spectroscopy for Monitoring Changes in Tissue Impedance
4.7.2. Fiber Optic Temperature Sensing for Monitoring Joule Heating Effects
4.7.3. Accelerometry Measurements for Muscle Excitation
4.8. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Temporal (h) | Pathological BBBDV (mm3) | MRI BBBDV (mm3) | Cerebral [EBD] (µg/g) | Serum [EBD] (µg/g) | BBBD Temporal Threshold (V/cm) |
---|---|---|---|---|---|
sham | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.2 ± 0.0 | 1494.0 ± 0.0 | ∞ |
1 | 81.2 ± 7.9 * | 84.1 ± 8.7 * | 18.5 ± 0.29 | 1318.3 ± 66.8 | 113.5 ± 8.2 |
24 | 47.1 ± 15.1 * | 40.9 ± 5.4 | 10.9 ± 0.45 | 1393.8 ± 122.0 | 174.9 ± 37.1 |
48 | 9.9 ± 1.1 | 10.4 ± 1.1 | 4.0 ± 0.31 | 1404.0 ± 115.1 | 432.7 ± 30.8 |
72 | 6.4 ± 1.1 | 5.8 ± 1.0 | 1.2 ± 0.13 | 1403.3 ± 145.1 | 542.5 ± 51.5 |
96 | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.3 ± 0.04 | 1400.5 ± 107.5 | ∞ |
Category | Survival (h) | Grade 1 | Grade 2 | Grade 2a | Grade 2b | Grade 3a | Grade 4 |
---|---|---|---|---|---|---|---|
sham | sham, n = 2 | 2 | 0 | 0 | 0 | 0 | 0 |
Immediate response | Burst100, n = 2 | 2 | 0 | 0 | 0 | 0 | 0 |
1, n = 2 | 2 | 0 | 0 | 0 | 0 | 0 | |
24, n = 4 | 4 | 0 | 0 | 0 | 0 | 0 | |
48, n = 4 | 4 | 0 | 0 | 0 | 0 | 0 | |
Delayed response | 72, n = 4 | 1 | 1 | 2 | 0 | 0 | 0 |
96, n = 4 | 0 | 0 | 2 | 2 | 0 | 0 | |
H-FIRE | H-FIRE, n = 2 | 0 | 0 | 0 | 0 | 1 | 1 |
Group | Time-Point (h) | Voltage/Distance Ratio (V/cm) | Number of Bursts |
---|---|---|---|
sham § | 1 | 0 | 0 |
1 * | 1 | 600 | 200 |
2 † | 24 | 600 | 200 |
3 † | 48 | 600 | 200 |
4 † | 72 | 600 | 200 |
5 * | 96 | 600 | 200 |
6, H-FIRE * | 1 | 1200 | 200 |
7, Burst100 * | 1 | 600 | 100 |
Score | Criteria: Brain Parenchyma Changes |
---|---|
0 | No lesions apparent |
1 | Superficial cerebral contusion, edema, electrode tracks, +/- hemorrhage; lesions limited to electrode tracks |
2 | Superficial cerebral contusion, edema, electrode tracks, +/- hemorrhage, inflammation; lesions limited to electrode tracks |
3 | Parenchymal hemorrhagic necrosis/ablation localized to electrode tracks/tips |
4 | Regional parenchymal hemorrhagic necrosis/ablation (necrosis around and remote from needle tracks) |
Criteria: Meningeal Changes * | |
a | Mild meningeal inflammatory infiltrates; limited locally to electrode insertion areas |
b | Moderate meningeal inflammatory infiltrates; meningeal involvement throughout surgical site |
c | Severe meningeal inflammatory infiltrates; diffuse meningitis extending beyond surgical field |
Material | Parameter | Value | Units |
---|---|---|---|
Brain tissue | Density, ρ | 1046 | kg/m3 |
Specific heat, c | 3630 | J/(kg∙K) | |
Thermal conductivity, k | 0.51 | W/(m∙K) | |
Blood perfusion coefficient, ω | 1.75 × 10−3 | 1/s | |
Insulation | Density, ρ | 1190 | kg/m3 |
Specific heat, c | 1470 | J/(kg∙K) | |
Thermal conductivity, k | 0.18 | W/(m∙K) | |
Electrical conductivity, σ | 2.5 × 1014 | S/m | |
Stainless steel | Density, ρ | 7850 | kg/m3 |
Specific heat, c | 475 | J/(kg∙K) | |
Thermal conductivity, k | 44.5 | W/(m∙K) | |
Electrical conductivity, σ | 4.0 × 1014 | S/m |
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Lorenzo, M.F.; Thomas, S.C.; Kani, Y.; Hinckley, J.; Lee, M.; Adler, J.; Verbridge, S.S.; Hsu, F.-C.; Robertson, J.L.; Davalos, R.V.; et al. Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation. Cancers 2019, 11, 1850. https://doi.org/10.3390/cancers11121850
Lorenzo MF, Thomas SC, Kani Y, Hinckley J, Lee M, Adler J, Verbridge SS, Hsu F-C, Robertson JL, Davalos RV, et al. Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation. Cancers. 2019; 11(12):1850. https://doi.org/10.3390/cancers11121850
Chicago/Turabian StyleLorenzo, Melvin F., Sean C. Thomas, Yukitaka Kani, Jonathan Hinckley, Matthew Lee, Joy Adler, Scott S. Verbridge, Fang-Chi Hsu, John L. Robertson, Rafael V. Davalos, and et al. 2019. "Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation" Cancers 11, no. 12: 1850. https://doi.org/10.3390/cancers11121850