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Mihalek, O.

Publications and source records attributed to Mihalek, O..

2 recordsLinked to original sources

The ultrastructure of subarachnoid trabeculae in non-human primates varies by tissue region within the central nervous system

The subarachnoid space (SAS) plays an important role in central nervous system (CNS) physiology, housing cerebrospinal fluid (CSF), providing nutrients, clearing waste, and protecting CNS tissues from injury. The SAS also contains an intricate arrangement of collagenous fibers, known as subarachnoid trabeculae, which serve as biomechanical support for the subarachnoid space and modulate the flow of CSF. Despite their myriad of roles in health and disease, the ultrastructure of trabeculae is incompletely described, with a specific gap in understanding how fiber structure varies across different regions of the CNS. In this work, we used optimized fixation techniques and scanning electron microscopy (SEM) imaging to study ultrastructural differences in trabeculae that were obtained from different regions of the nonhuman primate (NHP) brain and spinal cord. Qualitative assessments included evaluation of the relative prevalence of different kinds of fiber networks by region, leading us to a redefinition of terminology for fiber morphology. Quantitative measurements yielded dramatic differences in fiber diameter, density, and network porosity between different regions of the CNS. Broadly, trabeculae supporting cauda equina, cervical spinal cord, and exiting nerve roots were observed to have a very high density of small diameter fibers, whereas larger fibers and more complex arrangements were observed in other regions of the CNS. These data contribute to a growing field understanding of CNS-region specific differences in tissue ultrastructure.

neuroscience↗

Intrathecal infusion of hypertonic fluid enables CSF Flow Enhancement (CFE) to facilitate nanoparticle delivery to the brain and spinal cord

Intrathecal (IT) drug delivery, i.e., the infusion of substances directly into cerebrospinal fluid (CSF) by lumbar, ventricular, or cisternal access points, is one method that can be used to bypass the blood brain barrier (BBB), however, IT-administered substances also suffer from rapid turnover and poor tissue penetration. Although nanoparticles and colloids can circulate within the subarachnoid space to sustain the levels of encapsulated drug in CSF, their access to deep tissue regions remains incomplete. Here, we present a new method for enhancing CNS delivery of IT-administered nanoparticles. CSF Flow Enhancement (CFE) refers to the manipulation of CSF production, distribution, and clearance for therapeutic purposes. We tested the overarching hypothesis that infusion of hypertonic fluid adjacent to the choroid plexus would enhance fluid production and movement to improve the CNS delivery of IT-administered nanoparticles. Model polystyrene nanoparticles (100nm) were solubilized in aCSF of increasing tonicity (1-9X tonicity) and infused into the cisterna magna, after which tissues were removed to examine delivery to CNS tissues and peripheral organs. Our results demonstrate that an infusion of up to 4X hypertonic aCSF in 10uL is well tolerated and yields significant improvements in CNS localization of co-administered nanoparticles, more than doubling the delivery of nanoparticles to the ventral surfaces of the brain and sometimes dramatic (up to 10-fold) increases in delivery to specific tissue regions and surfaces of the CNS. Significantly, we provide early evidence that modulation of tonicity can define the parenchymal fate of IT administered colloids: while nanoparticles were not detected in the brain parenchyma of mice that received a standard infusion, parenchymal delivery was observed for the 2X condition, and extensive perivascular infiltration of nanoparticles was observed for the 4X condition. Lastly, we show that the delivery improvements achieved by CFE are generalizable across multiple sizes of polystyrene nanoparticle (20, 40, or 100nm). Collectively, this work describes a tonicity-based approach for achieving CFE by the intrathecal route, which we posit is a useful and potentially generalizable approach for improving CNS drug delivery.

bioengineering↗