Research ArticleDrug Delivery

Miniaturized neural system for chronic, local intracerebral drug delivery

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Science Translational Medicine  24 Jan 2018:
Vol. 10, Issue 425, eaan2742
DOI: 10.1126/scitranslmed.aan2742
  • Fig. 1 A miniaturized neural drug delivery system: The MiNDS.

    (A) Schematic illustration of a miniaturized neural drug delivery system (MiNDS) with an exploded view of the key device components (right, bottom inset) and with a magnified view of the borosilicate (BS) aligner tip aligning with the key device components in black arrow direction (left, top inset). (B) Image of L-MiNDS and S-MiNDS; electrical connection [tungsten (W) electrode] and the fluidic channels [borosilicate (BS)] are indicated. (C) Scanning electron microscopy (SEM) of the tip of L-MiNDS. (D) Magnified view of a BS aligner tip in the red dashed box in (C). The right inset shows the magnified view of W electrode in the yellow dashed box. (E) Representative confocal fluorescence images of horizontal brain slices showing the stab wound created by implanted MiNDSs, 8 weeks after implantation (n = 5 rats). Immunohistochemical staining for DNA (4′,6-diamidino-2-phenylindole, blue), astrocytes [glial fibrillary acidic protein (GFAP), green], microglia [ionized calcium binding adaptor molecule 1 (Iba1), red], neurons (NeuN, purple), and the merged signals are shown. Results are normalized to intensities 900 to 1100 μm away and averaged into 50-μm bins. The calculated error bars are the SDs.

  • Fig. 2 In vitro and in vivo functionality of the S-MiNDS.

    (A) Image of a MiNDS with U-junctions connected to two independently controlled iPrecio SMP-300 pumps. (B) Illustration of in vitro pump characterization setup with distinct layers of water and oil in the weighing dish as represented in green dashed box. (C) Line graph showing the mean infusion profiles of three infusion trials through S-MiNDS with flow rates 0.1, 1, and 10 μl/hour. End infusion (E.I.) (black dashed line) represents the end of infusion, and total volume (T.V.) (colored dashed lines) denotes the theoretical value of the volume infused. (D) Positron emission tomography (PET) images of Cu-64 in vivo delivery via an implanted MiNDS as seen in (A) (3 μCi/μl iPrecio infusion, 1.67-μl infusion at 10 μl/hour). Representative images at 5, 10, 15, and 20 min after Cu-64 injection show Cu-64 expression (fluorescence scale is depicted on the right). (E) Normalized fluorescence intensity in relation to position across the bolus. The diameter (w) of the bolus was determined using a three-dimensional (3D) region of interest (ROI), where the borders were defined as 10% of peak core intensity (I). (F) Normalized ROI sum fluorescence intensity at different times for identical Cu-64 infusions delivered into an agarose phantom (0.6% by weight) and in the rat brain through implanted S-MiNDSs using a syringe pump and an iPrecio pump (n = 3 trials; error bars represent SE). Statistical analysis was done using one-way ANOVA followed by Tukey post hoc test at each time point. Significance differences were only found at time = 20 min. *P < 0.05. DI, deionized.

  • Fig. 3 Tetrode trials and behavioral study in rats.

    (A) Firing rate histograms for 1-min bins of the recorded unit. The vertical black dashed lines indicate the start of saline infusion (first line at 30 min), the muscimol infusion (second line at 60 min), and the second muscimol infusion (third line at 90 min), respectively (n = 1). (B) Representations of sorted (orange) and unsorted (gray) action potentials based on peak values. Peaks 1 and 2 are the maximal value of waveforms measured by T-1 and T-2, respectively, during each period (preinfusion baseline, 22,928 waveforms; saline infusion, 20,940 waveforms; muscimol 1 infusion, 19,073 waveforms; and muscimol 2 infusion, 132 waveforms; n = 1 unit). (C) Averaged action potentials of a well-isolated unit (single unit) during each period (saline infusion, 20,940 waveforms; muscimol 1 infusion, 19,073 waveforms; and muscimol 2 infusion, 132 waveforms; n = 1 unit). Orange shading represents a band around the mean with a width of three SDs. (D and E) Picture and schematic illustration (orange dashed outline) of a rat with an implanted MiNDS targeting substantia nigra. Expanded view of black dashed line in (E) shows coronal cross section of the brain 5-mm posterior to the bregma. The red dot identifies the position of the MiNDS tip within substantia nigra. (F) Schematic of a rat inside an opaque chamber during the behavioral study. (G) Color-tracking map of a rat during the preinfusion, post-saline, and post-muscimol infusions periods. (H) Mean number of 180° clockwise (CW) and counterclockwise (CCW) turns during preinfusion, post-saline, and post-muscimol infusion periods (n = 3 rats, 2 trials per rat; error bars represent SE; **P < 0.0021). Statistical analysis was done using one-way ANOVA followed by Tukey post hoc test.

  • Fig. 4 In vivo MiNDS evaluation in an NHP.

    (A) Image of an experimental setup integrated with the head stage of a nonhuman primate (NHP). (B) Magnetic resonance imaging (MRI) image showing the estimated location of the L-MiNDS infusion and recording. Estimated coordinates of the L-MiNDS tip are 22 mm (anteroposterior) and 2 mm (mediolateral) from the bregma. (C) Unit rate histograms for 1-min bins. The first vertical orange dashed line indicates the start of artificial cerebrospinal fluid (aCSF) infusion (at 20 min), and the second vertical orange dashed line denotes the time of muscimol infusion (at 63.7 min) (n = 1 unit). (D) Average waveforms for units binned during each period (preinfusion baseline, 4593 waveforms; aCSF infusion, 51 waveforms; and muscimol infusion, 165 waveforms) with SD in gray shading.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/425/eaan2742/DC1

    Materials and Methods

    Fig. S1. Schematic illustration of fabricating a MiNDS.

    Fig. S2. Schematic illustration and SEM image of Hamilton needle.

    Fig. S3. Photographs of the steps for polishing and cleaning the tip of a BS channel.

    Fig. S4. SEM images of the components of a MiNDS.

    Fig. S5. SEM images of the components of a BS tip aligner.

    Fig. S6. SEM images of a completed MiNDS.

    Fig. S7. The electrical characterization of S- and L-MiNDS at 37°C in saline.

    Fig. S8. Chronic in vivo biocompatibility assessment.

    Fig. S9. Pump characterization setup.

    Fig. S10. Pump characterization protocol.

    Fig. S11. Infusion profiles of the iPrecio pump.

    Fig. S12. Large infusion characterization via PET.

    Fig. S13. Small infusion characterization via PET.

    Fig. S14. Infusion intensity and projection characterization via PET.

    Fig. S15. PET imaging after pump implantation.

    Fig. S16. Surgical procedure of an S-MiNDS with tungsten tetrode in vivo.

    Fig. S17. Distinctive infusion effect on firing rate in a rat.

    Fig. S18. Spectrograms from rat experiments.

    Fig. S19. Surgical procedure of an S-MiNDS and two pumps implantation in vivo.

    Fig. S20. Implanted pumps in a rat.

    Fig. S21. High-performance liquid chromatography absorbance spectrum at various concentrations of muscimol.

    Fig. S22. Behavioral study on rat models.

    Fig. S23. Average waveforms during distinctive infusions in a NHP.

    Fig. S24. Distinctive infusion effect on firing rate in a NHP.

    Fig. S25. LFP power analysis of a NHP trial.

    Fig. S26. Plot of dose/volume delivered in previous studies reported in the literature, injecting muscimol into the SN compared to MiNDS.

    Table S1. Statistical analysis for muscimol inhibition of spike activity for two sessions in two rats and for two sessions in a NHP.

    References (4953)

  • Supplementary Material for:

    Miniaturized neural system for chronic, local intracerebral drug delivery

    Canan Dagdeviren, Khalil B. Ramadi, Pauline Joe, Kevin Spencer, Helen N. Schwerdt, Hideki Shimazu, Sebastien Delcasso, Ken-ichi Amemori, Carlos Nunez-Lopez, Ann M. Graybiel, Michael J. Cima,* Robert Langer*

    *Corresponding author. Email: mjcima{at}mit.edu (M.J.C.); rlanger{at}mit.edu (R.L.)

    Published 24 January 2018, Sci. Transl. Med. 10, eaan2742 (2018)
    DOI: 10.1126/scitranslmed.aan2742

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Schematic illustration of fabricating a MiNDS.
    • Fig. S2. Schematic illustration and SEM image of Hamilton needle.
    • Fig. S3. Photographs of the steps for polishing and cleaning the tip of a BS channel.
    • Fig. S4. SEM images of the components of a MiNDS.
    • Fig. S5. SEM images of the components of a BS tip aligner.
    • Fig. S6. SEM images of a completed MiNDS.
    • Fig. S7. The electrical characterization of S- and L-MiNDS at 37°C in saline.
    • Fig. S8. Chronic in vivo biocompatibility assessment.
    • Fig. S9. Pump characterization setup.
    • Fig. S10. Pump characterization protocol.
    • Fig. S11. Infusion profiles of the iPrecio pump.
    • Fig. S12. Large infusion characterization via PET.
    • Fig. S13. Small infusion characterization via PET.
    • Fig. S14. Infusion intensity and projection characterization via PET.
    • Fig. S15. PET imaging after pump implantation.
    • Fig. S16. Surgical procedure of an S-MiNDS with tungsten tetrode in vivo.
    • Fig. S17. Distinctive infusion effect on firing rate in a rat.
    • Fig. S18. Spectrograms from rat experiments.
    • Fig. S19. Surgical procedure of an S-MiNDS and two pumps implantation in vivo.
    • Fig. S20. Implanted pumps in a rat.
    • Fig. S21. High-performance liquid chromatography absorbance spectrum at various concentrations of muscimol.
    • Fig. S22. Behavioral study on rat models.
    • Fig. S23. Average waveforms during distinctive infusions in a NHP.
    • Fig. S24. Distinctive infusion effect on firing rate in a NHP.
    • Fig. S25. LFP power analysis of a NHP trial.
    • Fig. S26. Plot of dose/volume delivered in previous studies reported in the literature, injecting muscimol into the SN compared to MiNDS.
    • Table S1. Statistical analysis for muscimol inhibition of spike activity for two sessions in two rats and for two sessions in a NHP.
    • References (4953)

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