Stabilization of CXCL12 (SDF-1α) via silk fibroin films enhances stem cell migration/retention and functional recovery after stroke

Brain pathologies such as ischemic stroke or traumatic brain injury (TBI) are among the most impactful diseases worldwide. In ischemic stroke, we currently lack truly effective treatments capable of delaying infarct progression, limiting lesion size or stimulating endogenous brain repair mechanisms to promote neurovascular remodeling and functional recovery. Two main barriers continue to limit the clinical translation of therapeutic molecules: the highly restrictive nature of the blood-brain barrier and that many bioactive molecules exhibit low stability at the target site, with half-lives shorter than the therapeutic window. In this study, we developed tunable silk fibroin (SF) films of variable concentration, fabricated via water annealing, that effectively preserve the functional activity of the chemokine CXCL12 (SDF-1α). The 2% SF formulation provided sustained release of SDF-1α for at least 7 days, promoting the <i>in vitro</i> migration of mesenchymal stem cells (MSCs) and low-density bone marrow mononuclear cells (LDBM), the latter containing hematopoietic stem cells. When implanted on the cortical surface, the SDF-1α-SF films successfully stimulated the guided migration of exogenously administered MSCs and LDBM from subcortical regions into the cerebral cortex. Furthermore, co-implantation of SDF-1α-SF films with MSCs or LDBM enhanced cell retention at the cortical site, effectively minimizing off-target dispersion. In a photothrombotic model of cortical ischemia, allowing precise control of lesion location and size, SDF-1α-SF films significantly reduced lesion volume and preserved neuronal function in the somatosensory cortex, as assessed by electrophysiology. Our findings provide proof of concept for using chemokine-releasing biomaterials to actively modulate stem cell migration and retention within the brain, offering strong potential for neuroprotection and tissue remodeling in areas at risk or already affected by damage.