Abstract
INTRODUCTION
Pre clinical interventions to the CNS require direct cranial administration of drugs for relevant therapeutic concentrations since the efficacy of systemic administration is hindered by 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, with sub-millimeter precision, in preselected areas. This method is a revolutionary way to deliver cellular therapy to delicate or inoperable regions obviating the need for invasive surgical intervention.
METHODS
MRgFUS mediates BBB opening when low intensity FUS is applied to brain vasculature containing circulating microbubbles. This causes high intensity oscillation leading to a pore formation in BBB. hMSCs 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 for 120 seconds were administered on the left hemisphere. Each animals contralateral brain served as its own control.
RESULTS
>We demonstrate that MRgFUS augments permeability of BBB. Each animal (n = 3) received 3 cavitation parameters ranging from .4-1MPa in situ pressures at time points 2, 6 and 24 hrs. Immunohistochemistry identified hMSC localization on sonicated points. Further analysis showed blood cell extravasation and capillary damage due to the indices being sonicated so 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.
CONCLUSION
The global hurdle of systemic therapy due to the BBB makes access of therapeutics, let alone cellular therapy to the brain parenchyma, 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.
In Situ Forming Gelatin Hydrogels-Directed Angiogenic Differentiation and Activity of Patient-Derived Human Mesenchymal Stem Cells
