Devices for cell transplantation into the central nervous system: Design considerations and emerging technologies

Abstract

Successful use of cell-based therapies for the treatment of neurological diseases is dependent upon effective delivery to the central nervous system (CNS). The CNS poses several challenges to the delivery of cell-based therapeutics, including the blood-brain barrier, anatomic complexity, and regional specificity. Targeted delivery methods are therefore required for the selective treatment of specific CNS regions. In addition, CNS tissues are mechanically and physiologically delicate and even minor injury to normal brain or spinal cord can cause devastating neurological deficits. Targeted delivery methods must therefore minimize tissue trauma. At present, direct injection into brain or spinal cord parenchyma promises to be the most versatile and accurate method of targeted CNS therapeutic delivery. While direct injection methods have already been employed in clinical trials of cell transplantation for a wide variety of neurological diseases, there are many shortcomings with the devices and surgical approaches currently used. Some of these technical limitations may hinder the clinical development of cell transplantation therapies despite validity of the underlying biological mechanisms. In this review, we discuss some of the important technical considerations of CNS injection devices such as targeting accuracy, distribution of infused therapeutic, and overall safety to the patient. We also introduce and discuss an emerging technology - radially branched deployment - that may improve our ability to safely distribute cell-based therapies and other therapeutic agents to the CNS. Finally, we speculate on future technological developments that may further enhance the efficacy of CNS therapeutic delivery.

Keywords: Cell transplantation; Parkinson's disease; radially branched deployment; stereotactic injection.

Figure 1

The need for neurosurgical instrumentation that minimizes cranial penetrations. (a) Current straight cannula cell delivery devices require multiple cranial penetrations to increase cell distribution (green) within a target region (yellow). Each penetration carries a distinct risk of hemorrhage and as many as eight penetrations per hemisphere have been performed in clinical trials of cell transplantation to the CNS. Since this is the most serious complication associated with procedures of this type, a more ideal injection device would require only a single transcortical penetration to distribute cells to the entire target region, as in (b). Image provided in part by Kenneth Xavier Probst of XavierStudio

Figure 2

Problems associated with infusate reflux. (a) Direct injection of a cell suspension (blue) into the target region (yellow) with a straight cannula device can result in reflux of infusate up the penetration tract (see arrows). This inability to accurately distribute therapeutics minimizes the achievable distribution volume (green) and results in a loss of therapeutic material. Moreover, reflux along the penetration tract delivers cells to unintended target locations, which may have adverse effects and lead to negative or mixed therapeutic results. (b) An ideal injection device would minimize reflux and achieve delivery to the entire target region (green). Image provided in part by Kenneth Xavier Probst of XavierStudio

Figure 3

Extensional forces experienced by cells upon injection through a syringe and needle. The diameter of an injection syringe is typically larger than that of the attached needle. As a cell (blue) passes from a syringe to a needle, it will experience increasing velocities along its length, causing the cell to stretch and possibly rupture. These extensional forces may therefore decrease cell viability during injection. A greater differential between the diameters of the syringe and needle will result in greater extensional forces, while a longer needle will increase the time a cell experiences extensional forces

Figure 4

Inconsistencies in cell dosing related to the sedimentation of cells in suspension. (a) Cells (green) in a carrier fluid (blue) sediment over time, increasing the cellular concentration of the suspension at the most dependent portion of the delivery syringe. This gradient of cell density can lead to inconsistent cell dosing if multiple injections are performed from the same syringe, as is commonly done when grafting multiple cellular deposits along a single penetration tract (b). Sedimentation may therefore result in a higher cell density at the first injection site (1) and decreasing cell densities at the subsequent injection sites (2 and 3). Such variability is difficult to predict and may adversely affect outcomes

Figure 5

Diffusion of a cell suspension after injection into the brain. (a) Host cell bodies (gray) and interstitial space (yellow) comprise the CNS parenchyma. During an injection procedure, a cannula can mechanically create a potential space within the interstitium. A cell suspension (blue and magenta) can be deposited into this potential space, as shown in (b). The carrier fluid (magenta) will begin to diffuse into the interstitium, while the cells will only experience limited, if any, movement into the interstitial space (c)

Figure 6

Interventional magnetic resonance imaging-compatible radially branched deployment device (a). All components are made of FDA-approved, non-paramagnetic materials (b). Proximal control elements allow simple opening and closing of the distal side port (c). (d) iMRI RBD with the Clearpoint SMARTframe platform. (e) Deployed cell delivery catheter

Figure 7

Schematic illustrating the use of RBD to deliver cells to a larger human brain target. A cylindrical cannula introduced by any modern stereotactic frame can be precisely rotated around the axis of the initial trajectory and retracted to more superficial brain regions without incurring additional neural damage. Thus, the ability to deploy a cell delivery catheter perpendicular to initial trajectory along multiple radii and depths allows one to efficiently “aborize” larger brain target regions such as the putamen (pink) via a single transcortical brain penetration. Image provided in part by Kenneth Xavier Probst of XavierStudio