3d model of a skull

EDEN2020 study finds direction of fluid injection in the brain, affects drug uptake

March 30, 2021

EDEN2020 seminal paper published that answers the question, how do fluids flow inside the brain and why do we need steerable needles as the ultimate solution for cancer therapy?

EDEN2020 partners have finally proven what they set out to do over 5 years ago: that directionality of needle insertion plays a crucial role when infusing drugs into the brain. These findings published in the IEEE Transactions on Biomedical Engineering journal, investigated at a microscopic level, how easily fluid can flow in brain white matter – tissue composed of nerve fibres (axons) and the extracellular matrix, through which information within the central nervous system is transmitted. Researchers from Imperial College London and Politecnico di Milano, through EDEN2020, an EU-funded Horizon2020 project, found that the direction of a fluid injected into the brain impacts the uptake of the fluid into the specific area of the brain.

This work is the first of its kind. The hypothesis had only been previously documented via computer simulations with experimental proof still missing. It wasn’t until this innovative work from EDEN2020 researchers that there is now experimental evidence that supports the use of a steerable needle for drug delivery. EDEN2020 coordinator and Co-Director of the Hamlyn Centre, Prof Ferdinando Rodriguez y Baena of Imperial College London said of this seminal work, “It took us quite some time to get to the bottom of the complex pipework within the brain, but we can now finally confirm that tissue permeability is indeed directional and so optimising needle tip delivery can influence and improve drug injection”.

Steerable needles for treating brain cancer

The findings published in the landmark paper titled Infusion Mechanisms in Brain White Matter and their Dependence on Microstructure: An Experimental Study of Hydraulic Permeability has been the work of partners in EDEN2020 for the past five years to understand brain structures and functions in order to develop treatment for deadly diseases affecting the brain. One of the most aggressive and frequently diagnosed forms of brain cancer, Glioblastoma multiforme (GBM) has led to 250,000 deaths worldwide and is incredibly challenging to treat. Locating and removing or shrinking tumours in an area like the brain, which has 86 billion neurons and 100 trillion connections has been one of the hardest challenges. Current conventional treatments are limited by their capacity to deliver therapeutic drugs to kill malignant tissue, which can be buried deep in the brain and hard to get to, and not affect healthy tissue. This is compounded by the limited understanding of how fluids are transported and move inside the brain.

The EDEN2020 team have been working to address these limitations with the development of advanced surgical technologies such as steerable needles for convection enhanced delivery (CED) systems – an innovative technique that generates a pressure difference at the tip of a needle to deliver therapeutics directly through tissue (Mehta et al. 2017).

A prerequisite for the optimal success of CED is knowing how at a microscopic scale, drugs flow through tissue while under a positive pressure gradient, like water being pushed through a hose using a pump. There have been ideas and computational results floating around the scientific space highlighting the effects of drug flow in the tissue based on the different directions of the fibres in brain white matter, also known as microstructural anisotropy however, any experimental proof was missing until the recent work of researchers from the EDEN2020 consortium.

The research team explored the infusion mechanisms in brain white matter which revealed that tissue offers different resistance to drug flow injected from different directions. Therefore, it is important to inject a drug from a specific direction i.e. parallel to the axons in white matter, in order to achieve maximum drug delivered to the target, a tumour for example.

New pathways for cancer therapy

Leading these experiments, Dr Asad Jamal of Imperial College London said, “this landmark work will change the scientific community’s perception about targeted drug injection into the central nervous system (CNS), which was often considered uniformly distributed in all directions”. Talking about the significance of the experiments into directional fluid flow in the brain, otherwise known as localised hydraulic permeability, Prof Daniele Dini of Imperial, who supervised the work said, “this not only provides a pathway to develop our understanding of the targeted drug delivery and drug distribution in the CNS tissue, but also a valuable set of information for scientists interested in modelling the brain and highlights the need to explore this phenomenon at microscopic scale when it comes to experiments.”

This work further emphasises the need to develop surgical technologies which not only overcome the already known limitations of drug distribution, such as the presence of blood-brain barrier (BBB), but also to be capable of steering to inject the drug along a specific direction. Prof Lorenzo Bello, who leads the clinical team at Università di Milano, can see this conclusive data impacting the medical field further. “These findings support the clinical data reporting that diffusion of tumour cells occurs prevalently along white matter tracts; the study of how the tumour has changed the brain connectivity is therefore relevant for orienting the distribution of infused drugs, targeting the tumour bulk along with infiltrative areas, enhancing the anti-neoplastic activity”. Prof Bello goes on to comment that “the available technologies failed in doing so and the use of a curve catheter may represent the crucial technological adjunct to perfectly achieving this goal”.

The paper is freely available:

Jamal et al., “Infusion Mechanisms in Brain White Matter and their Dependence on Microstructure: An Experimental Study of Hydraulic Permeability,” in IEEE Transactions on Biomedical Engineering, DOI: 10.1109/TBME.2020.3024117.