Preclinical research suggests that stem cell therapy could help restore functional function in stroke. Selecting the optimal route of administration is crucial as it affects cell survival, biodistribution, and therapeutic efficacy. There have been several administration methods ranging from intracerebral, intraventricular, subarachnoid, intra-arterial, intraperitoneal, intravenous, and intranasal. While these routes offer potential benefits, the most effective method has yet to be determined.

Fig.1. Routes of administration of stem cells in preclinical studies and clinical applications. (Rodríguez-Frutos, et al., 2016)

Ace Therapeutics is dedicated to helping clients develop stem cell-based therapies for stroke to reduce neuroinflammation and regenerate damaged brain tissue and nerve cells lost due to stroke. In addition, we offer experimental stroke models to help our clients explore the most feasible, safe, and effective routes of administration of stem cell therapies, as well as experimental studies of the safety, efficacy, and mechanism of action of these therapeutic effects.

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• Development of Stem Cell-Based Therapy for Stroke

Routes of Administration of Stem Cells in Stroke

Intracerebral Route

Intracerebral administration had long been considered the best route to transplant neural stem cells to the brain because they self-regenerated, turned into neural cells, and were able to replace neurons lost to stroke. In addition to replacing neurons, neural stem cells are also paracrine therapeutic cells, release growth factors, and deliver mRNA. In animal models, stem cells from other organs have also been tried: embryonic stem cells, induced pluripotent stem cells (iPSCs), and mesenchymal stem cells, have also been explored for intracerebral administration in animal models.

While success rates in achieving mature neuronal phenotypes are relatively low (2–20%), intracerebral delivery demonstrates significant efficacy, with approximately one-third of transplanted cells migrating toward damaged regions. This approach is particularly effective in subcortical stroke, where endogenous neural precursor cells from the subventricular zone (SVZ) migrate to the peri-infarct striatum. Although the role of endogenous neurogenesis in recovery remains uncertain, intrastriatal injection of human iPSCs has been shown to enhance recovery, as these cells survive and differentiate into immature and mature neurons, proving the feasibility of this method for subcortical strokes.

Intraventricular and Subarachnoid Route

Less invasive methods, such as intraventricular and subarachnoid administration, offer alternatives to direct intracerebral implantation for stem cell therapy after stroke. These approaches have shown potential for enhancing cell survival, recovery, and migration to lesion areas. While intracerebral grafting allows for neural replacement, its safety remains a concern.

There are also limitations to both the intracerebral and intraventricular routes of stem cell delivery for brain repair, including invasiveness, scarcity of cells, immunity rejection, and the fate of cells transplanted into the brain. These problems are huge obstacles to translating cell therapy into clinical use.

Intra-arterial Route

In animal models, intra-arterial injections of stem cells have been efficacious for stroke, where a catheter takes the cells into the carotid artery and delivers them to the brain injury site. But usually only 1-10 percent of transplanted cells actually make it to the injury area. These cells support brain repair by replacing neural connections, producing trophic factors, and enhancing endogenous neurogenesis.

In recent years, several subtypes of cell therapies have been developed using intra-arterial administration in experimental stroke animal models. While many studies have reported successful recovery, others have emphasized complications, such as microemboli, as well as conflicting findings regarding the effects of cell dose, size, and infusion rate. For example, high infusion rates or cell doses can lead to embolic events and reduced cerebral blood flow, but these effects remain inconsistent across studies. Further research is needed to address safety concerns, optimize delivery parameters, and determine the most effective ways to translate cell therapy into clinical practice.

Intravenous Route

The intravenous (IV) route of stem cell delivery, which can be clinically feasible and useful instead of intra-arterial, has similar protective effects without the complications. Preclinical research has shown promising results, with stem cells from bone marrow stromal cells, bone marrow mononuclear cells, fat-derived mesenchymal stem cells and iPSCs all boosting recovery, shrinking lesion size, boosting brain plasticity and decreasing inflammation and apoptosis following stroke.

Although intravenous cell therapy shows potential, its effects can vary depending on factors like age. For instance, aged brains exhibit reduced regenerative capacity, though recent evidence suggests that iPSCs can survive, differentiate, and improve recovery in aged animal models. Contrary to earlier beliefs that transplanted cells primarily replace lost neurons, studies reveal that many intravenously administered stem cells remain undifferentiated or migrate to the spleen rather than the brain. This migration appears to modulate the immune response, reducing inflammation, edema, and apoptosis.

Intraperitoneal Route

A recent study comparing intraperitoneal and intravenous stem cell administration found that the route significantly affects cell distribution after brain injury. Intravenous delivery resulted in higher cell presence in the lung and brain for mesenchymal stem cells, and in the spleen, liver, and lung for mononuclear cells, compared to the intraperitoneal route.

Intranasal Delivery

Intranasal delivery is a novel route for cell-based stroke therapy, primarily studied in experimental animal models. Intranasal administration of bone marrow mesenchymal stem cells improves cell homing to ischemic areas, reduces lesion volumes, restores blood-brain barrier integrity, increases brain plasticity, and enhances functional recovery in both ischemic and hemorrhagic stroke models. So far, there is no trial of intranasal stem cell therapy in humans.

Advantages and Disadvantages of Routes of Administration in Stroke Treatment

1. Rodríguez-Frutos, B., et al. (2016). Stem cell therapy and administration routes after stroke. Translational stroke research, 7, 378-387.