Radially Branched Deployment for More Efficient Cell Transplantation at the Scale of the Human Brain

Abstract

Background: In preclinical studies, cell transplantation into the brain has shown great promise for the treatment of a wide range of neurological diseases. However, the use of a straight cannula and syringe for cell delivery to the human brain does not approximate cell distribution achieved in animal studies. This technical deficiency may limit the successful clinical translation of cell transplantation. Objective: To develop a stereotactic device that effectively distributes viable cells to the human brain. Our primary aims were to (1) minimize the number of transcortical penetrations required for transplantation, (2) reduce variability in cell dosing and (3) increase cell survival. Methods: We developed a modular cannula system capable of radially branched deployment (RBD) of a cell delivery catheter at variable angles from the longitudinal device axis. We also developed an integrated catheter-plunger system, eliminating the need for a separate syringe delivery mechanism. The RBD prototype was evaluated in vitro and in vivo with subcortical injections into the swine brain. Performance was compared to a 20G straight cannula with dual side ports, a device used in current clinical trials. Results: RBD enabled therapeutic delivery in a precise ‘tree-like’ pattern branched from a single initial trajectory, thereby facilitating delivery to a volumetrically large target region. RBD could transplant materials in a radial pattern up to 2.0 cm from the initial penetration tract. The novel integrated catheter-plunger system facilitated manual delivery of small and precise volumes of injection (1.36 ± 0.13 µl per cm of plunger travel). Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. While reflux of infusate along the penetration tract was problematic with the use of the 20G cannula, RBD was resistant to this source of cell dose variability in agarose. RBD enabled radial injections to the swine brain when used with a modern clinical stereotactic system. Conclusions: By increasing the total delivery volume through a single transcortical penetration in agarose models, RBD strategy may provide a new approach for cell transplantation to the human brain. Incorporation of RBD or selected aspects of its design into future clinical trials may increase the likelihood of successful translation of cell-based therapy to the human patient.

Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus

“…More recently, novel cannulae were proposed to further enhance the delivery efficiency. For instance, a micro-fabricated catheter with MR compatibility was evaluated in vivo for intraparenchymal delivery 25 ; a radially branched cannula was designed for efficient delivery at the scale of the human brain 26 . Nevertheless, all cannula-based approaches require invasive procedures and may cause various complications.…”

Interventional Magnetic Resonance Imaging-guided Cell Transplantation Into the Brain With Radially Branched Deployment

“…11 The iMRI-guided RBD platform makes such catheter exchange very simple. Given this aspect of the RBD device design, a separate cell delivery catheter can be used to dispense a cell aliquot that is specific to each radial location.…”

“…Cell viability before and after their passage through the RBD delivery catheter was performed as previously described. 11 Briefly, the cell delivery catheter was backfilled with 50 μl of each cell suspension and dispensed into a polystyrene test tube at a rate of 5 μl/minutes. Dead cells were stained with Sytox Red (Life Technologies, Grand Island, NY) and quantified via flow cytometry (LSR II; BD Bio-sciences, San Jose, CA).…”

“…3 While much recent translational research has been focused on improving the quality and quantity of human cell types for transplantation, 4 there has been very little innovation of the surgical tools and techniques used for cell delivery to the human brain. [5][6][7][8][9][10][11] If unresolved, faults with cell delivery may contribute to the failure of clinical trials despite robust preclinical evidence and a compelling biological rationale.…”

“…25 We recently described a metal device prototype that enables the radially branched deployment (RBD) of a cell delivery catheter at multiple points along a cannula tract. 11 By varying the depth, rotation, and radial distance of catheter deployment, one could use RBD to deliver cells in a customizable "tree-like" pattern branched from a single cannula insertion. iMRI would facilitate RBD-based delivery to anatomically large and/or complex brain target regions, as the delivery could be monitored with real-time imaging, and transgression of critical brain structures could be more precisely avoided.…”