Benchmarking the ERG valve tip and MRI Interventions Smart Flow neurocatheter convection-enhanced delivery system's performance in a gel model of the brain: employing infusion protocols proposed for gene therapy for Parkinson's disease

Abstract

Convection-enhanced delivery (CED) is an advanced infusion technique used to deliver therapeutic agents into the brain. CED has shown promise in recent clinical trials. Independent verification of published parameters is warranted with benchmark testing of published parameters in applicable models such as gel phantoms, ex vivo tissue and in vivo non-human animal models to effectively inform planned and future clinical therapies. In the current study, specific performance characteristics of two CED infusion catheter systems, such as backflow, infusion cloud morphology, volume of distribution (mm(3)) versus the infused volume (mm(3)) (Vd/Vi) ratios, rate of infusion (µl min(-1)) and pressure (mmHg), were examined to ensure published performance standards for the ERG valve-tip (VT) catheter. We tested the hypothesis that the ERG VT catheter with an infusion protocol of a steady 1 µl min(-1) functionality is comparable to the newly FDA approved MRI Interventions Smart Flow (SF) catheter with the UCSF infusion protocol in an agarose gel model. In the gel phantom models, no significant difference was found in performance parameters between the VT and SF catheter. We report, for the first time, such benchmark characteristics in CED between these two otherwise similar single-end port VT with stylet and end-port non-stylet infusion systems. Results of the current study in agarose gel models suggest that the performance of the VT catheter is comparable to the SF catheter and warrants further investigation as a tool in the armamentarium of CED techniques for eventual clinical use and application.

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…Newly emerging convection enhanced delivery (CED) technique offers an alternate method to deliver a high concentration of biological therapeutic agents that otherwise do not cross the blood-brain barrier [5].Despite the promise of CED, several technical barriers such as those relating to the infusate trajectory reflux and poor drug distribution have limited its effectiveness [6]. Drug therapy using direct CED in brain been reported for treating glioma [7] and epilepsy [8].…”

“…Furthermore, from clinical perspective, evidence makes it clear that miRNAs may be potent therapeutic tools that can manipulate cell state and molecular processes in order to enhance functional recovery. In this paper, we will review the extensive history of the use of modeling CED in the brain and spinal cord and discuss the role of siRNA and miRNA therapies in alleviating NP (Figure 1 [5,6].Similarly, infusion pressure, flow rate, and volume changes affect infusion success be evaluated across catheter designs [12]. Methods of predicting and detecting infusion protocol variance such as monitoring infusion line pressure changes and altering the infusion to avoid aberrant infusion morphology and catheter reflux are helpful in maximizing therapy are testable in the surrogate brain model.…”

“…Methods of predicting and detecting infusion protocol variance such as monitoring infusion line pressure changes and altering the infusion to avoid aberrant infusion morphology and catheter reflux are helpful in maximizing therapy are testable in the surrogate brain model. Furthermore, the strategies for the movement of an infusion catheter within the target tissue with respect to order of infusion versus movement and catheter design are testable [5]. Commercially available systems for low volume, pressure monitored infusions may also be tested within the surrogate brain to determine infusion pump requirements for planned and future infusion protocols, including operating requirements such as MRI safety of the infusion system [11].…”

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

“…Once the agarose gel has solidified (approximately 1-2 hr), add 1 cm of water to the top of the gel and refrigerate. It is best to use the gel within 24-48 hr of mixing, but it can be stored for up to a week refrigerated 10 . 4.…”

“…Advances in catheter design 10 , infusion technique 11 , line pressure monitoring 2 , and real time MRI monitoring to correct for brain shift 12,13 , optimize multiple collinear infusions 14 , and monitor for infusate loss 15 have increased the safety and efficacy of the treatment 10 . Additional importance has been placed on the catheter design and infusion strategy including flow rate.…”