Late diagnosed ischemic stroke is a leading cause of serious long-term disability and the 5th leading cause of death in the United States (U.S.). Ischemic stroke is often characterized by an early cytotoxic type of edema that occurs within minutes following ischemic followed by ionic edema caused by water uptake through the intact blood brain barrier (BBB). A vasogenic form of edema occurs hours later resulting from damage to the BBB which initiates a secondary wave of cytotoxic edema that leads to neuronal injury. Brain swelling (edema) and increased intracranial pressure is common among ischemic stroke patients. Clinically significant cerebral edema occurs frequently in patients with malignant middle cerebral artery infarction (MMI). Patients with MMI have a high mortality rate near 80%, primarily due to herniation and compression of the brain stem. At the extreme, about 10% of these patients experiencing MMI may be eligible for decompressive hemicraniectomy (DC). While DC can provide immediate relief of intracranial pressure due to edema, little else can be done and the patient is completely dependent on a natural rate of recovery. This proposal seeks to develop and test a novel device to reduce cerebral edema, improve neurological outcomes for MMI patients that undergo DC. The proposed work will be to ultimately design a topical osmotic therapy device (OTD, patent pending 20,130,115,267), specifically for DC for MMI patents to: 1) control cerebral edema, 2) stimulate an effective convective flux across tissue in eminent danger of damage near the necrotic core, and 3) deliver a neurorestorative agent, anti-inflammatory neuregulin (NRG-1) directly to the exposed cerebral tissue. This hollow-fiber based OTD will be in direct contact with the brain tissue after a DC, which enhances fluid and mass transfer in damaged tissues and reduces edema.
Three specific aims will be pursued: (1) to develop and examine the efficacy of an OTD to reduce cerebral edema and induce mass transport in the tissue; (2) to evaluate the effectiveness of delivering NRG-1 at prescribed times and to determine if the combined strategy for reducing cerebral edema and delivering NRG-1 is as effective as the individual approaches; and (3) to evaluate the neurological outcomes following the use of the device. The proposed work will characterize the transport of fluids in cerebral tissues following application of this device after craniectomy in a middle cerebral artery occlusion (MCAO) animal ischemic stroke model. Optical coherence tomography (OCT) and magnetic resonance imaging (MRI) will be used to track edema within the cerebral tissues due to the OTD device in the absence and presence of treatment with NRG-1. Overall, this work has the potential to lead to a novel paradigm to reverse cerebral edema and improve neurological outcome for MMI patents who have undergone DC. If successful, this study would aid in the development of a new FDA-approved device for the treatment of ischemic stroke in humans.
The objective in this application is to develop a novel osmotic transport device (OTD) to enhance flux in cerebral tissue for patients with severe ischemic stroke and thereby reducing cerebral edema. We will also use the OTD to deliver neuregulin-1 to prevent secondary edema and neuronal injury in brain tissues. If successful, this study would aid in the development of a new FDA-approved device for the treatment of ischemic stroke in humans.
