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Principal Investigator: Tatiana Segura
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $485,635
Funding agency: National Institute of Neurological Disorders and Stroke
Summary
Stroke is the leading cause of adult disability in the US. There are no therapeutic options beyond physical therapy
to reduce disability burden; thus, new therapeutic options are highly needed. The stroke cavity is the region of
the brain that dies after stroke and does not spontaneously regenerate. We are interested in designing injectable
hydrogel formulations that can promote brain tissue repair after stroke and propose that intra core injection can
be an ideal delivery location. We engineered an angiogenic hydrogel that re-vascularizes the necrotic stroke
cavity, promotes vascular and neurological tissue formation within the stroke core, and promotes behavioral
improvement. Achieving any type of brain repair in the stroke cavity is remarkable. We cannot be sure if
behavioral improvement occurred because of this new tissue formation or due to improved peri-infarct plasticity.
Nevertheless, behavioral improvement was observed between 12 and 16-weeks. We believe that to bring this
technology closer to clinical utility, we must be able to improve the recovery timeline to closer to 4 weeks post
stroke. In this proposal, we will investigate synapse formation and improved mechanical support as a way to
improve recovery timeline after cortical ischemic stroke. Astrocytes play a critical role in synapse formation and
pruning; thus, we will investigate several approaches to modulate this cell population in the brain post stroke and
also the delivery of secreted astrocyte proteins that are known to play a role in synapse formation. This proposal
builds upon our preliminary data that porous scaffolds promote astrocyte infiltration into the material post stroke,
that integrin binding can dictate differentiation of neuroprogenitor cells into astrocytes, and that TSP-1 can
promote similar levels of synapse formation as astrocytes. In particular, we will study how scaffold microstructure
and incorporation of bioactive signaling molecules can promote astrocytic infiltration or differentiation of
progenitor cells towards an astrocytic lineage (Aim 1), how the incorporation of our current angiogenic strategy
into a porous scaffold impacts behavioral improvement (Aim 2), how the delivery of TSP-1 from our porous
scaffolds influences brain repair and behavioral improvement post stroke. Overall, we aim to engineer a pro-
synaptic material that could improve on the timeline and degree of behavioral improvement after stroke.
Terms: <21+ years old><Adult><Adult Human><Apoplexy><Area><Arg-Gly-Asp><Arginine-Glycine-Aspartic Acid Cell Adhesion Domain><Astrocytes><Astrocytus><Astroglia><Axon><Behavioral><Biocompatible Materials><Biomaterials><Biomedical Engineering><Birth><Blood Vessels><Body Tissues><Brain><Brain Nervous System><Brain Vascular Accident><Brain region><Cell Body><Cells><Cerebral Stroke><Cerebral cortex><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinical><Data><Development><Encephalon><Engineering><Environment><Experimental Designs><Formulation><Gel><Generalized Growth><Generations><Goals><Growth><Heparin><Heparinic Acid><Human><Hyaluronic Acid><Hydrogels><Immune response><Immunological response><Infarction><Infiltration><Inflammatory Response><Injectable><Injections><Integrin Binding><Ischemic Stroke><Location><Mechanics><Medical><Mice><Mice Mammals><Modern Man><Monitor><Murine><Mus><Natural regeneration><Necrosis><Necrotic><Nerve Cells><Nerve Unit><Neural Cell><Neural Stem Cell><Neuro rehabilitation><Neurocyte><Neurologic><Neurological><Neurons><Neurorehabilitation><Parturition><Physiatric Procedure><Physiatrics><Physiatry><Physical Medicine><Physical Medicine Procedure><Physical Therapeutics><Physical therapy><Physiotherapy><Play><Population><Porosity><Proteins><RGD (sequence)><RGD Cell Adhesion Domain><RGD Domain><RGD Motif><RGD Tripeptide Sequence><RGD peptide><RGD tripeptide><Recovery><Regeneration><Rehabilitation Medicine><Repair Material><Robotics><Role><Signaling Molecule><Speed><Stroke><Structure><Synapses><Synaptic><TSP-1><TSP1><Technology><Therapeutic><Thrombospondin 1><Time><Tissue Growth><Tissues><VEGF><VEGFs><Vascular Endothelial Growth Factors><adulthood><after stroke><arginyl-glycyl-aspartic acid><astrocytic glia><axon growth><axonal growth><bio-engineered><bio-engineers><bioengineering><biological engineering><biological material><brain attack><brain repair><brain tissue><cerebral vascular accident><cerebrovascular accident><clinical translation><clinically translatable><design><designing><developmental><disability><disability burden><host response><immune system response><immunoresponse><improved><in vivo><infarct><inflammatory modulation><integrin bound><interest><mechanic><mechanical><nano particle><nano-sized particle><nanoparticle><nanosized particle><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurological rehab><neurological rehabilitation><neuron progenitors><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><neurorehab><neurorehabilitative><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel technologies><novel therapeutics><novel therapy><ontogeny><particle><post stroke><poststroke><progenitor cell differentiation><progenitor cell markers><progenitor differentiation><progenitor markers><progenitor stem cell markers><programs><regenerate><repair><repaired><response><revascularization><scaffold><scaffolding><social role><stem and progenitor differentiation><stem cell biomarkers><stem cell differentiation><stem cell markers><stroked><strokes><synapse><synapse formation><synaptogenesis><timeline><tissue repair><vascular>