Ramped-rate vs. continuous-rate infusions: An in vitro comparison of Convection Enhanced Delivery protocols

Abstract

BackgroundConvection enhanced delivery (CED) is a technique using infusion convection currents to deliver therapeutic agents into targeted regions of the brain. Recently, CED is gaining significant acceptance for use in gene therapy of Parkinson’s disease (PD) employing direct infusion into the brain. CED offers advantages in that it targets local areas of the brain, bypasses the blood-brain barrier (BBB), minimizes systemic toxicity of the therapeutics, and allows for delivery of larger molecules that diffusion driven methods cannot achieve. Investigating infusion characteristics such as backflow and morphology is important in developing standard and effective protocols in order to successfully deliver treatments into the brain. Optimizing clinical infusion protocols may reduce backflow, improve final infusion cloud morphology, and maximize infusate penetrance into targeted tissue.PurposeThe purpose of the current study was to compare metrics during ramped-rate and continuous-rate infusions using two different catheters in order to optimize current infusion protocols. Occasionally, the infusate refluxes proximally up the catheter tip, known as backflow, and minimizing this can potentially reduce undesirable effects in the clinical setting. Traditionally, infusions are performed at a constant rate throughout the entire duration, and backflow is minimized only by slow infusion rates, which increases the time required to deliver the desired amount of infusate. In this study, we investigate the effects of ramping and various infusion rates on backflow and infusion cloud morphology. The independent parameters in the study are: ramping, maximum infusion rate, time between rate changes, and increments of rate changes.MethodsBackflow was measured using two methods: i) at the point of pressure stabilization within the catheter, and ii) maximum backflow as shown by video data. Infusion cloud morphology was evaluated based on the height-to-width ratio of each infusion cloud at the end of each experiment. Results were tabulated and statistically analyzed to identify any significant differences between protocols.ResultsThe experimental results show that CED rampedrate infusion protocols result in smaller backflow distances and more spherical cloud morphologies compared to continuous-rate infusion protocols ending at the same maximum infusion rate. Our results also suggest internal-line pressure measurements can approximate the time-point at which backflow ceases.ConclusionOur findings indicate that ramping CED infusion protocols can potentially minimize backflow and produce more spherical infusion clouds. However, further research is required to determine the strength of this correlation, especially in relation to maximum infusion rates.

Comparative Morphometry of the Wisconsin Miniature Swine^TM Thoracic Spine for Modeling Human Spine in Translational Spinal Cord Injury Research

“…The data are presented as mean ± SEM. show promise for targeted delivery of therapies into the brain [25][26][27][28], can be developed and refined for improving the effectiveness of therapies administered into the spinal cord [25,29].…”

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, 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.…”

Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue

“…5,6,7,8 Infusion protocols and catheter design have an important impact on delivery, and CED is a valid alternative employed for systemic administration of agents in clinical trials. CED infusion performance in agarose gel has previously been benchmarked using an agarose gel model while testing methods of delivery of multiple spherical payloads to fill a non-spherical target, a process that may influence treatment.…”