Mrigfus non-invasively opens the neonatal blood-brain-barrier and can be used to deliver different sized molecules.

Abstract

Background: The blood brain barrier (BBB) regulates the internal cerebral environment and protects it from the peripheral system. Delivery of stem cells across the BBB is a hurdle for administering therapies without resorting to invasive neurosurgery. Using MRI-guided focused ultrasound (MRIgFUS), we can non-invasively open the BBB and deliver different sized agents to the brain parenchyma without penetrating the skull. In order to test this, we performed MRIgFUS and then delivered different size dextran beads to assess the size of BBB opening. Method(s): In postnatal day 10 rat pups, microbubbles were injected via the tail vein and the BBB was opened by MRIgFUS using sonication pressures of ~0.2-0.8 MPa. Contrast (gadolinium) and fluorescent dextran beads (70 kDa, 2000 kDa) were injected and the pup underwent MRI to visualise the BBB opening. Result(s): Sonication at ~0.2 MPa resulted in the BBB opening enough to pass the 70 kDa dextran through to the parenchyma but not the 2000 kDa dextran. Sonication at higher pressures (0.8 MPa) opened the BBB enough for the 2000 kDa dextran to cross into parenchyma, however, this higher pressure caused haemorrhage seen on MRI and in gross pathology at post-mortem. Conclusion(s): MRIgFUS does not appear to be a safe technology to use in neonates for cell therapy as the vascular bed is too immature and cannot withstand acoustic pressures strong enough to cross a large 2000 kDa molecule through to the parenchyma. It may be suitable for smaller molecule drug delivery.