Poster W7 - Evaluation of an Osmotic Transport Device for the Treatment of Cerebral Edema in a Rat Model of Penetrating Traumatic Brain Injury

Introduction: Therapeutics for traumatic brain injury (TBI)-induced cerebral edema represent a critical gap for battlefield point-of-injury care. Animal studies show that an osmotic transport device (OTD) can reduce acute edema development through surface treatment of edematous tissue that removes water via direct osmotherapy. However, the safety and efficacy of OTDs need to be further tested. The objective of this study was to examine the acute effect of OTD treatment on cerebral edema, intracranial pressure (ICP) and neuropathology in a rat model of penetrating TBI.

Materials and

Methods: The OTD was composed of a flat sheet membrane with a molecular weight cutoff of 10 kDa and non-reactive chemical composition. A biocompatible housing was constructed via SLA (stereolithography) methods that was designed to rest on top of and penetrate the cranium. An agar-based hydrogel was placed in contact with the membrane and the tissue to maintain osmotic pressure. A total of 350 g/L BSA (bovine serum albumin) dissolved in aCSF (artificial cerebral spinal fluid) were used to create the osmotic gradient.
The acute effects of OTD treatment on ICP and CPP were defined in a rat penetrating traumatic brain injury (pTBI) model. ICP and mean arterial pressure (MAP) were measured in adult male Sprague-Dawley rats prior to and following right unilateral pTBI. Animals were randomly assigned to four groups: Sham (no injury), Injury only (no device), OTD with isotonic fluid (OTDiso), and OTD with hypertonic fluid (OTDhyp) and treated from 1 to 5hr post-injury. Cerebral edema was measured using the wet-dry method. The impact of OTD on cerebral edema progression was characterized by MRI during and following a 72hr treatment with isotonic or hypertonic fluid. Lesion volume, neuroinflammation, and neuronal damage were assessed.

Results, Conclusions, and Discussions: ICP was decreased in the hypertonic treated group compared to both isotonic and pTBI-only controls by approximately 1 mmHg, however, this change was not significant. While not statistically significant, the ICP trends are promising in acute TBI stages. As expected, all treatment groups remained above sham values.

No significant difference was found in edema volume or hemorrhage determined via MRI, however, the OTD treatment, with isotonic or hypertonic treatment, elicited a reduction in brain water content in the ipsilateral hemisphere via the wet-dry method. Histological assessment demonstrated a significant reduction of IBA1 levels in the striatum, and silver stain analysis also indicated a trending reduction of neuronal damage.
MRI data for the 3-day animal trial indicate that there is no significant difference in cerebral edema progression over the time period.

These results provide evidence that OTDhyp treatment following pTBI has the potential to reduce ICP and improve neuropathologies. MRI data results indicate that while the device does not directly influence the reduction of cerebral edema it does not further harm the animal and may indicate positive neurological outcomes. The histology data suggesting reduced neuronal damage in the OTDhyp group support the previous data and MRI results.

Previous studies have indicated that the effectiveness of the OTD cannot be fully characterized by a reduction in brain water content. Histological data regarding the IBA1 receptor suggest a reduction in the inflammatory response and could indicate a positive neurological outcome. The neuroprotective effects of the OTD on treating neuroinflammation and neuronal damage to improve on neurological outcomes following pTBI will be examined further. A 7-day trial and a porcine study are currently in progress which will examine the effectiveness of the OTD.

Acknowledgements (Optional): Financial support from US Army MTEC and from the Jacques S. Yeager, Sr. Professorship.