Stroke is one of the main causes of death in the US and post-stroke treatment options remain limited. Ischemic stroke is caused by a blood clot that compromises blood supply to the brain, rapidly leading to tissue death at the core of the infarcted area surrounded by a hypoxic and nutrient-starved region known as the penumbra. Recent evidence suggests that astrocytes in the penumbral region play a dual role in stroke response, promoting further neural and tissue damage or improving tissue repair depending on the microenvironment. Thus, astrocyte response in the hypoxic penumbra could promote tissue repair after stroke, salvaging neurons in the affected area and contributing to cognitive recovery. However, the complex microenvironment of ischemic stroke, characterized by gradients of hypoxia and nutrients, poses a unique challenge for traditional in vitro models, which in turn hinders the development of novel therapies. To address this challenge, we have developed a novel, polystyrene-based microfluidic device to model the necrotic and penumbral region induced by an ischemic stroke. We demonstrated that when subjected to hypoxia, and nutrient starvation, astrocytes within the penumbral region generated in the microdevice exhibited long-lasting, significantly altered signaling capacity including calcium signaling impairment.