Three-dimensional nonlinear finite element model to estimate backflow during flow-controlled infusions into the brain

Abstract

<jats:p> Convection-enhanced delivery is a technique to bypass the blood–brain barrier and deliver therapeutic drugs into the brain tissue. However, animal investigations and preliminary clinical trials have reported reduced efficacy to transport the infused drug in specific zones, attributed mainly to backflow, in which an annular gap is formed outside the catheter and the fluid preferentially flows toward the surface of the brain rather than through the tissue in front of the cannula tip. In this study, a three-dimensional human brain finite element model of backflow was developed to study the influence of anatomical structures during flow-controlled infusions. Predictions of backflow length were compared under the influence of ventricular pressure and the distance between the cannula and the ventricles. Simulations with zero relative ventricle pressure displayed similar backflow length predictions for larger cannula-ventricle distances. In addition, infusions near the ventricles revealed smaller backflow length and the liquid was observed to escape to the longitudinal fissure and ventricular cavities. Simulations with larger cannula-ventricle distances and nonzero relative ventricular pressure showed an increase of fluid flow through the tissue and away from the ventricles. These results reveal the importance of considering both the subject-specific anatomical details and the nonlinear effects in models focused on analyzing current and potential treatment options associated with convection-enhanced delivery optimization for future clinical trials. </jats:p>

Insights into Infusion-Based Targeted Drug Delivery in the Brain: Perspectives, Challenges and Opportunities

“…Backflow is one of the main drawbacks of CED as it would significantly decrease the drug volume and should be avoided [ 114 , 115 , 116 ]. To model this phenomenon, a fluid–solid interaction method should be an ideal option as this involves overall deformation of the tissue driven by the flow, and there is a clear boundary between the solid phase and the fluid phase where the fluid–solid interface develops.…”

“…To model this phenomenon, a fluid–solid interaction method should be an ideal option as this involves overall deformation of the tissue driven by the flow, and there is a clear boundary between the solid phase and the fluid phase where the fluid–solid interface develops. However, fluid–solid interaction has not been applied due to numerical challenges introduced by the unknown time-varying hydraulic pressure between the tissue and the catheter [ 116 ]. Some alternative methods were then proposed.…”

“…Benefitting from the deformability of the two layers of solid elements, the deformation of fluid–solid boundaries was able to be described. This method was also adopted and extended to 3D in [ 116 ]. The most important factors that determine the accuracy of this treatment are the properties of these two layers of elements, which require the elements to be able to possess fluidic behaviours.…”

Convection Enhanced Delivery in the Setting of High-Grade Gliomas

“…To assess this, Orozco et al proposed a novel 3D non-linear biphasic finite element model of a healthy human brain to quantify the extent of reflux during CED, where cannula diameter and placement could be adjusted. This model was able to predict length of backflow, accounting for both patientspecific structural factors and the non-linear deformation of brain parenchyma 66 .…”

Convection-Enhanced Delivery in silico study for personalized brain cancer treatment

“…Their study combined patient-specific parameters and brain structure using a poro-elastic model with information about the anatomy, heterogeneities, and anisotropy of the tissue from diffusion tensor imaging (DTI) data 16 . Other computational studies have been employed to investigate a catheter design and placement, infusion flow rate and how drug distribution, backflow and reflux are affected 6,17,18 , providing guidelines for effective CED 17 . Studies also focused on the engineering of a novel backflow-free catheter, allowing the therapeutics to reach an increased concentration to the site of delivery and a more predictable distribution that is critical for patient care 6 .…”