Strategies for the Delivery of Multiple Collinear Infusion Clouds in Convection-Enhanced Delivery in the Treatment of Parkinson's Disease

Abstract

Background: Delivery of multiple collinear payloads utilizing convection-enhanced delivery (CED) has historically been performed by retraction of a needle or catheter from the most distal delivery site. Few studies have addressed end-infusion morphology and associated payload reflux in stacked and collinear infusions, and studies comparing the advancement with the retraction mode are lacking. Objective: To compare advancement versus retraction mode infusion results. Methods: Infusion cloud pairs were created with the advancement and retraction technique in agarose gel using both open end-port SmartFlow™ (SF) and valve tip (VT) catheter infusion systems. Backflow, radius of infusion, and morphology were assessed. Results: Infusions with the SF catheter, in contrast to the VT catheter, exhibited significantly more backflow in retraction mode at the shallow infusion site. Infusion morphology differed with the second infusion after retraction: the infusate at the proximal site first filling the channel left by the retraction and then being convected into gel in a pronouncedly non-spherical shape during the second infusion. Conclusions: Significant differences in cloud morphology were noted with respect to external catheter geometry with retraction versus penetration between infusions in an agarose gel model of the brain. Further study is warranted to determine optimal protocols for human clinical trials employing CED with multiple collinear payloads.

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

“…CED-based in vitro, ex vivo and in vivo animal models have led to active genetherapy trials for treating Parkinson disease (PD)and are supported by histological studies on disease pathology [9].Use of MRI navigation in some clinical trials, helps accurately targeting and providing real time monitoring of viral vector delivery (rCED). Several researcher labs including ours adopted different small and large animal models exploring use of CED in brain [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The results from these studies are promising with a suggestion of superiority over intrathecal (IT) injection.…”

“…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]. Findings during research on CED catheter design and development of CED stroke treatment lead to the merger of ultra-sound and CED.CED in regard to volume distributed (Vd), volume infused (Vi) and location using in vitro model, ex vivo brain animal models, in vivo insect, mouse, rat, and non-human primate models of PD have been reported in an effort to validate techniques for benchmarking infusion characteristics across models [9,10] and adopted for use in human gene-based therapy trials [10].…”

“…CED is a method for direct infusion of therapeutics not able to cross the blood-CNS barrier and may be a method for delivering macromolecules such as siRNA [11].Use of a syringe pump system may allow for low-flow infusions. To ensure success, pressure monitoring may be required.…”

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

“…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.…”

Commentary: Current status of intratumoral therapy for glioblastoma

“…In fact, a retrospective review of catheter placement on patient outcomes in the PRECISE trial showed that overall catheter placement scores did not correlate with local tumor control, progression free survival, or overall survival 32 . The additional issue of infusion backflow also exists in CED, though catheter design has recently been improved with use of multiple ports, backflow-reducing technology, as well as variable injection rates [33][34][35][36] . Overall, the pattern of drug dispersal during CED, especially around inhomogeneous peritumoral tissue, has proven to be unpredictable 37 , but is steadily improving.…”