An Implantable, Intracerebral Osmotic Pump for Convection-Enhanced Drug Delivery in Glioblastoma Multiforme

Reed Berlet¹Azur Azapagic²Neilank K Jha³Daniil Aksenov^4,5,6Jade Bookwalter⁷Ata Ullah⁷George Bobustuc⁸John Lee⁹Himanshu Sant¹⁰John McDaid^1,6Matthew Walker⁴Jill Shea^11,7Dylan Graff^12,3Ann K Barlow^13,14Roberta Frigerio^13,14Daniel Aliee^15,3Clint Bailes¹⁶Bruce K Gale^2,7Julian E Bailes^1,3,6*

• ¹Department of Neurosurgery, Endeavor Health, Evanston, United States
• ²Department of Mechanical Engineering, The University of Utah, Salt Lake City, United States
• ³Deep Brain BCI, Wilmington, United States
• ⁴Department of Radiology, Endeavor Health, Evanston, United States
• ⁵Department of Anesthesiology, Endeavor Health, Evanston, United States
• ⁶University of Chicago Pritzker School of Medicine, Chicago, United States
• ⁷Department of Biomedical Engineering, The University of Utah, Salt Lake City, United States
• ⁸Intent Medical Group, Endeavor Health Advanced Neurosciences Institute, Arlington Heights, United States
• ⁹Department of Pathology, Endeavor Health, Evanston, United States
• ¹⁰Department of Chemical Engineering, The University of Utah, Salt Lake City, United States
• ¹¹Department of Surgery, The University of Utah School of Medicine, Salt Lake City, United States
• ¹²Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada
• ¹³Research Institute, Endeavor Health, Evanston, United States
• ¹⁴Pritzker School of Medicine, Chicago, United States
• ¹⁵School of Kinesiology and Health Science, York University, Toronto, Canada
• ¹⁶Louisiana State University, Baton Rouge, United States

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.