Scdt-09. Focal Enhanced Delivery of Systemically Administered Therapeutic Human Mesenchymal Stem Cells Using Mri-guided Disruption of the Bbb With Focused Ultrasound
Year: 2017
Type: conference-abstract
Abstract: Pre-clinical interventions to the CNS often require direct cranial administration to reach relevant therapeutic concentrations but cranial opening is not always justified. Systemic administration is required yet application is often hindered due to the difficulty in penetrating the blood-brain barrier (BBB). We used MR-guided Focused Ultrasound (MRgFUS) to deliver primary-patient derived mesenchymal stem cells (hMSCs) for the first time in preselected areas of the brain with sub-millimeter precision. MRIgFUS is a revolutionary way to deliver cellular therapy to delicate or inoperable regions obviating the need for invasive surgical intervention. MRgFUS mediates BBB opening when low intensity FUS is applied to brain vasculature containing circulating microbubbles where the oscillation initiates BBB opening at site of FUS pulse. Human MSCs isolated from our patients were injected intracardially in mice as a proof-of-principal delivery system. Under guidance of MRI, 0.4-1MPa in situ pressures at 1 MHz, 1ms bursts and 1Hz pulse repetition frequency of 120 seconds, left hemisphere of mice was sonicated while the contralateral hemisphere served as control. We demonstrate MRgFUS-mediated permeability of BBB. Each animal (n=3) received 3 cavitation parameters ranging from .4-1MPa in situ pressures at 2, 6 and 24hrs. Immunohistochemistry identified hMSC localization on sonicated points. Further analysis showed blood cell extravasation and capillary damage due indices sonicate close together causing a larger sheer force from the fluid stream of injected microbubbles. The consequence is a cavitation pore larger than intended, necessitating further optimization. There were no observed behavioral complications after sonication and no hMSCs localization in non-pulsed regions demonstrating precise localization and no off-target delivery. Hurdles of systemic therapy due to BBB makes access of therapeutics nearly impossible. This study investigates for the first time the utility of FUS to non-destructively permeabilize the BBB by creating a transient pore big enough for hMSC access.
Source: Neuro-Oncology
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4238255605