Comparison of different transplantation routes and timing for stem cell therapy in stroke

BACKGROUND: Stem cell transplantation holds therapeutic promise for stroke, yet its clinical translation is hindered by unresolved challenges in administration routes, timing, and poor cell engraftment and survival. METHODS: This is a narrative (non-systematic) review. Registered clinical studies were identified in ClinicalTrials.gov, the European Union Clinical Trials Register and the Chinese Clinical Trial Registry, and were supplemented by targeted PubMed searches for the preclinical and mechanistic literature. Records were eligible if they evaluated stem cell transplantation for ischemic or hemorrhagic stroke and reported the delivery route and/or the transplantation time window; records reporting neither were excluded. Because direct head-to-head clinical comparisons of routes and time windows are scarce, registry data and selected preclinical studies were synthesised descriptively rather than pooled, and no meta-analysis was performed. RESULTS: Each administration route presents a distinct profile. Intravenous injection is minimally invasive and simple but limited by pulmonary sequestration, low cerebral engraftment, and high cell dose requirements. Intra-arterial infusion offers improved targeting but shares similar limitations. Intrathecal delivery allows direct central nervous system access with concentrated doses but carries risks of cerebrospinal fluid leakage and an inflammatory microenvironment. Intracerebral implantation ensures high local engraftment and long-term survival with minimal cell numbers but is invasive and poses risks of hemorrhage and further tissue injury. Intranasal administration is non-invasive with a wide therapeutic window yet exhibits extremely low delivery efficiency. Regarding timing, intravenous and intra-arterial routes are primary in the acute phase; in the subacute phase these routes remain common, alongside intrathecal administration; for chronic stroke, intracerebral and intrathecal transplantation are the predominant strategies in clinical trials. CONCLUSION: This review synthesizes two decades of progress and persisting challenges in stem cell therapy for stroke, focusing on delivery strategies and timing. Successful clinical translation will require further large-scale, multicenter prospective studies to optimize these critical parameters.