Abstract
Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 μL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.
Highlights
Neurological disorders affect over 100 million people in the United States and pose a significant societal and economic burden, costing more than $800 billion/year in the U.S alone [1]
The MRI compatibility of the convection enhanced delivery (CED) cannula and lack of susceptibility-induced imaging artifacts are of paramount importance to ensure accuracy of targeting and volume distributions (VD) quantification
In order to fully realize this potential, the issue of targeted and broad infusate distribution via CED must be addressed via novel engineering solutions to the delivery cannula systems
Summary
Neurological disorders affect over 100 million people in the United States and pose a significant societal and economic burden, costing more than $800 billion/year in the U.S alone [1]. The standard of care for NDs of the CNS are symptomatic pharmacological therapies based on systemic delivery of large molecular weight (MW) drugs administered either orally or intravenously. A successful strategy to bypass the BBB and increase delivery efficiency is based on intraparenchymal (IPa) injections directly into the target site in the brain. This technique is called convection enhanced delivery (CED) and relies on the convective flow generated by a positive pressure gradient imposed by a syringe pump to deliver the infusate through a catheter and into the target brain tissue. CED has been successfully used in IPa delivery of a large number of substances, including chemotherapeutics [6, 7], viral vectors [8,9,10,11,12], nanocarriers [13, 14], and neurotrophic factors [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
