J Korean Med Sci.  2022 Aug;37(31):e244. 10.3346/jkms.2022.37.e244.

IntraBrain Injector (IBI): A StereotacticGuided Device for Repeated Delivery of Therapeutic Agents Into the Brain Parenchyma

• Lee J
• Lee S
• Jung W
• Kim GB
• Kim T
• Seong J
• Jang H
• Noh Y
• Lee NK
• Lee BR
• Lee JI
• Choi SJ
• Oh W
• Kim N
• Lee S
• Na DL

• KMID: 2532319
• DOI: http://doi.org/10.3346/jkms.2022.37.e244

Abstract

Background
To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma.
Methods
We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection.
Results
We compared the planned vs. insertion trajectory of IBI to the hippocampus. With a similarity of 0.990 ± 0.001 (mean ± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study.
Conclusion
Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.

Keyword

Brain Parenchyma; Precise Targeting; Long-term Implantable Device; Repeated Administration; Neurodegenerative Disease

Figure

• 

  Fig. 1 Scheme of IBI implantation and stem cell administration. In each group, MRI was taken at 1) baseline (after marker screw insertion), 2) pre-injection (before stem cell administration), and 3) post-injection (after stem cell administration).IBI = IntraBrain Injector, MRI = magnetic resonance imaging.

• 

  Fig. 2 Determination of insertion trajectory and design of the surgical guide and adaptor. (A) The target area (the hippocampus in this study, marked in purple) was determined based on coronal view MRI after screw insertion. To determine the ideal trajectory, 3D-rendered images of the skull and brain were reconstructed. (B) An ideal insertion trajectory was considered one that allowed insertion of the IBI into the gyrus with minimal muscle detachment. (C) The surgical guide and adaptor were designed based on the location of three marker screw landmarks on the skull, reflecting the skull curvature. (D) The surgical guide (blue) was positioned to exactly locate the drilling point of the burr hole. (E) The adaptor was positioned in line with the burr hole, not only to fill the gap between the flat bottom surface of IBI and the curved skull surface, but to prevent the IBI from invading the brain surface.IBI = IntraBrain Injector, MRI = magnetic resonance imaging, MR = magnetic resonance.

• 

  Fig. 3 Surgical procedures for IBI implantation in beagles. An illustration of operational procedures for the IBI. (A) Skin and muscles above the skull were incised minimally along the midline. Location of the screws on the skull that had been installed before IBI implantation was confirmed. Beagles were placed on a stereotaxic frame for the surgery. (B) A 3D-printed surgical guide (coloured in green) was placed on the skull, according to the location of marker screws. (C) Using the surgical guide, a burr hole (coloured in red) was drilled. (D) A round-shaped adapter (coloured in blue) was anchored above the burr hole. (E) The IBI was placed on the adapter.IBI = IntraBrain Injector.

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  Fig. 4 Validation of target approach accuracy. Validation of target accuracy is shown in 3D rendered views and coronal MRI in (A) group 1 (six injections), (B) group 2 (three injections), and (C) group 3 (single injection). The white arrow shows a signal indicative of haemorrhage after surgery in the MRI of Subject 6-1.MRI = magnetic resonance imaging.

• 

  Fig. 5 MRI used for evaluation. MRI results of pre- and post-injection in (A) six-injection group, (B) three-injection group, and (C) single injection group.MRI = magnetic resonance imaging.Failed results marked with superscript ‘a’ indicate an uncertain signal and those marked with superscript ‘b’ indicate signals detected further than 2 mm from the target area.

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