An implantable, intracerebral osmotic pump for convection-enhanced drug delivery in glioblastoma multiforme

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Background Glioblastoma multiforme (GBM; WHO Grade 4) is an aggressive brain tumor that invariably recurs after surgical resection, chemoradiation, and adjuvant chemotherapy. Treatment is limited, in part, because the blood-brain barrier (BBB) restricts entry of chemotherapeutic agents to the brain. Introducing drugs directly into the brain circumvents the BBB, but diffusion of these typically large drug molecules within brain parenchyma is limited. Convection-enhanced delivery (CED), based on the principles of bulk flow, can achieve drug distribution over a wider area to target residual cancer cells and thus remains a promising technique for treating GBM and other neuro-oncologic pathologies. Here, we propose a new method that combines direct brain delivery and CED using a fully implantable, microfluidic pump placed at the time of initial resection surgery. Methods In this initial proof-of-concept study, we evaluated the function of a 3D-printed pump in an in vitro system and in vivo in a rat C6 glioma model. Results In vitro osmosis-driven distribution of a high molecular-weight marker dye extended up to 18 mm from the pump with minimal reflux, including under simulations of increased intracranial pressure. In vivo, MRI imaging demonstrated wide distribution of superparamagnetic iron oxide particles from a pump implanted after the resection of a C6 glioma. Histological staining indicated that pump implantation did not cause additional inflammatory changes compared to controls. Conclusion This preliminary study demonstrated the feasibility of using an implantable, osmosis-driven pump to bypass the BBB and provide targeted delivery for treatment of GBM.

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