Biomaterials Strategies to Promote Functional Recovery After Ischemic Stroke

Duke University, Durham NC

Investigators

Linked publications, trials & patents

Abstract

Summary Stroke is the leading cause of disability in the US, and beyond neuroprotective measures during the acute window (minutes to hours after stroke), there are no therapeutic options apart from physical therapy. The pathogenic cause of stroke-related disability is the death of neuronal tissue which forms a non-regenerative stroke cavity in the brain. However, this cavity is surrounded by a peri-infarct area in which regenerative programs are upregulated, creating an opportunity for bioengineered therapies to synergize with native repair pathways. To this end, my lab has pioneered the use of intracranial biomaterials-based strategies which promote functional recovery and brain regeneration after stroke. Noting that the peri-infarct is rich in activated astrocytes, we recently investigated the use of extracellular vesicles (EVs) derived from activated rat astrocytes (A-EVIL-4/C1q) as bioactive agents that we covalently bound to our microporous annealed particle (MAP) biomaterial platform and injected intracranially. We found that these reactive rat astrocyte EVs (rA-EVIL-4/C1q), when delivered from MAP gel (rA- EVIL-4/C1q-MAP), promoted repair on the cellular, tissue, and functional level. These promising findings now prompt us to study reactive astrocyte EVs in combination with MAP as a potentially translational therapy. We hypothesize that MAP gel is needed to induce brain repair, but that systemic delivery of reactive astrocyte EVs via intravenous delivery in combination with local MAP treatment can in part recapitulate the therapeutic effects of A-EVIL-4/C1q-MAP - and can be used as a means of repeated A-EVIL-4/C1q administration. To make our technology more clinically relevant, first we will characterize A-EVIL-4/C1q generated from human induced pluripotent stem cells (hiPSCs) in vitro and in vivo (Aim 1). We will then test multiple delivery routes and schedules to interrogate our hypothesis (Aim 2). We will also examine the effects of A-EVIL-4/C1q with and without MAP gel in an aged animal model to understand the therapeutic implications of the technology in a model with decreased reparative capacity (Aim 3). Our proposed therapy is feasibly translational; EVs from other cell sources, such as mesenchymal stem/stromal cells, are currently in clinical trials to treat neurological conditions, including stroke. Concomitantly, our strategy is highly innovative; no clinical approach has combined EVs and biomaterials for neurological disease, nor have hiPSC-astrocyte-EVs been studied as a therapeutic. Most importantly, no product has reached the market to lessen the burden of stroke-related disability for patients and their caregivers, and our technology holds strong potential to do so. The success of our proposal will move us significantly closer to a therapeutic strategy that targets brain regeneration rather than neuroprotection as a treatment for ischemic stroke.