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.