Shear Containment of BDNF within Molecular Hydrogels Promotes Human Stem Cell Engraftment and Postinfarction Remodeling in Stroke

Abstract

Improved control over spatiotemporal delivery of growth factors is needed to enhance tissue repair. Current methods are limited–requiring invasive procedures, poor tissue targeting, and/or limited control over dosage and duration. Incorporation into implantable biomaterials enables stabilized delivery and avoids burst release/fluctuating doses. Here, the physical forces of fibrils formed by self-assembly of epitope-containing peptides are exploited. This biomimetic hydrogel is loaded with neurotrophic factor BDNF via a shear-induced gel–solution transition, unique to noncovalent hydrogels. This results in a biomaterial with three desirable features: a nanofibrillar scaffold, presentation of a laminin epitope, and slow release of BDNF. In a stroke-injury model, synergistic actions of this trimodal strategy on the integration of transplanted human neural progenitor cells, and protection of peri-infarct tissue are identified. These BDNF-functionalized hydrogels promote the integration of transplanted human embryonic stem cell–derived neural progenitors–resulting in larger grafts with greater cortical differentiation, appropriate for neuronal replacement. Furthermore, BDNF promotes the infiltration of host endothelial cells into the graft to augment vascularization of the graft, and adjacent penumbra tissue. These findings demonstrate the benefits of multifaceted tissue-specific hydrogels to provide biomimetics of the host tissue, while sustain protein delivery, to promote endogenous and graft-derived tissue repair.