Person:

Bleier, Benjamin

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson’s disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

Objectives To characterize the temporal distribution and resolution rate of postoperative complications from endoscopic skull base surgery.

Design Retrospective review of patients undergoing endoscopic resection of paranasal sinus or skull base neoplasm from 2007 to 2013.

Setting Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary Cranial Base Center.

Participants Fifty-eight consecutive patients.

Main Outcome Measures Postoperative complications were categorized as cerebrospinal fluid (CSF) leak, pituitary, orbital, intracranial, or sinonasal. Complications were temporally categorized as “perioperative” (within 1 week), “early” (after 1 week and within 6 months), or “delayed” (after 6 months).

Results The most common perioperative complications were diabetes insipidus (19.0%), CSF leak (5.2%), and meningitis (5.2%), with resolution rates of 75%, 100%, and 100%, respectively. Overall, CSF leak occurred in 13.8% of patients and resolved in all cases. A total of 53.8% of all complications were evident within 1 week of surgery. Chronic rhinosinusitis was the most common delayed complication (3.4%). Hypopituitarism and delayed complications were less likely to resolve (p = 0.014 and p = 0.080, respectively).

Conclusions Monitoring of complications after endoscopic skull base surgery should focus on neurologic complications and CSF leak in the early postoperative period and development of chronic rhinosinusitis in the long term. Late-onset complications and hypopituitarism are less likely to resolve.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous upper airway disease with multiple etiologies. Clinically, CRSwNP can be classified into either eosinophilic or non-eosinophilic subtypes. The eosinophilic phenotype of CRSwNP is widely thought to be highly associated with recurrence of nasal polyps or surgical failure. Epithelial cells have a crucial role in the development of Th2-biased airway diseases. Recent studies have shown that a wide range of external stimuli such as allergens and microorganisms can elicit the release of epithelial-derived Th2-driving cytokines and chemokines. Protease activity is a feature common to these multiple environmental insults and there is growing evidence for the concept that an imbalance of proteases and protease inhibitors in the epithelial barrier leads to both the initiation and maintenance of chronic eosinophilic airway inflammation. In this review, we analyze recent work on the role of proteases in the development of the sinonasal mucosal type 2 immune response with an emphasis on the molecular pathways promoting adaptive Th2 cell immunity.

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.