Bypassing the blood–brian barrier using established skull base reconstruction techniques

Abstract

Background: Neurological disorders represent a profound healthcare problem accounting for 6.3% of the global disease burden. Alzheimer's disease alone is expected to impact over 115 million people worldwide by 2050 with a cost of over $1 trillion per year to the U.S. economy. Despite considerable advances in our understanding of the pathogenesis and natural history of neurological disorders, the development of disease modifying therapies have failed to keep pace. This lack of effective treatments is directly attributable to the presence of the blood–brain and blood–cerebrospinal fluid barriers (BBB and BCSFB) which prevent up to 98% of all potential neuropharmaceutical agents from reaching the central nervous system (CNS). These obstacles have thereby severely limited research and development into novel therapeutic strategies for neurological disease. Current experimental methods to bypass the BBB, including pharmacologic modification and direct transcranial catheter implantation, are expensive, are associated with significant complications, and cannot be feasibly scaled up to meet the chronic needs of a large, aging patient population. Transmucosal drug delivery: An innovative method of direct CNS drug delivery using heterotopic mucosal grafts was described. This method is based on established endoscopic skull base nasoseptal flap reconstruction techniques. The model has successfully demonstrated CNS delivery of chromophore-tagged molecules 1000 times larger than those typically permitted by the BBB. Conclusions: This innovative technique represents the first described method of permanently bypassing the blood–brain barrier using purely autologous tissues. This has the potential to dramatically improve the current treatment of neurological disease by providing a safe and chronic transnasaldelivery pathway for high molecular weight neuropharmaceuticals. Keywords: Blood–brain barrier, Transnasal drug delivery, Skull base reconstruction, Mucosal flap