Intra-Arterial Delivery of Cell Therapies for Stroke

I don't understand so you'll have to ask your fucking failures of stroke associations to explain the strategy behind this and when it will be available and its efficacy.

Raphael Guzman, Miroslaw Janowski, Piotr Walczak

Download PDF

https://doi.org/10.1161/STROKEAHA.117.018288

Stroke. 2018;49:1075-1082

Originally published April 18, 2018

• Article
• Figures & Tables
• Supplemental Materials
• Info & Metrics

• brain
• cell size
• liver
• neuroprotection
• spleen

Great achievements in acute stroke care have been made, to a large extent, because of increased stroke awareness. Earlier arrival of patients at dedicated stroke centers leads to a better chance of successful treatment. Nevertheless, to date, the therapeutic options for acute stroke are still limited to intravenous tissue-type plasminogen activator, mechanical thrombolysis, or delivery of fibrinolytics. Although those therapies have had a significant impact on stroke outcome, there is still a remarkable lack of adjunct therapeutic options, such as neuroprotection and neurorestoration. Cell therapies represent a new investigational approach for the treatment of stroke. Preclinical reports are abundant, and controlled clinical trials have begun to be performed around the globe. Many critical questions remain to be answered, and a consortium of scientists and clinicians is joining forces to discuss open issues and provides potential recommendations based on the best available knowledge.¹

One of the many critical questions is about the ideal route of delivery in terms of efficacy, safety, timing of delivery, and methods by which to monitor the process. Published clinical studies have mainly used intracerebral transplantation and intravenous injection. Smaller case series have reported intra-arterial cell delivery. Selection of the cell delivery route should be based on the primary therapeutic mechanisms. Systemic effects would favor intravenous route. If recovery depends on cell–cell interactions then intraparenchymal or intra-arterial injection may be most beneficial. There seems to be a good rationale for intravascular delivery. It is less invasive than intracerebral transplantation, it is repeatable, it would allow for a systemic biological effect, and could lead to a widespread distribution in the affected brain regions.² This potentially would compare favorably to the focal delivery achieved with stereotactic transplantation. Even in cases of permanent arterial occlusion, which is rare, a significant number of cells can home into the ischemic brain through collateral circulation. With an increasing number of intra-arterial catheter interventions for stroke performed, it would also seem that intra-arterial cell injection would be ideally suited in the stroke setting, as well as being quite feasible. Preclinical data suggest that intra-arterial cell injection leads to a greater number of cells targeting the ischemia. The main reason for this is that cells bypass filtering organs, such as the lung, the spleen, and the liver.³ Preclinical studies have also demonstrated that targeted delivery to the ischemic brain has well-defined molecular mechanisms, attracting cells from the intravascular to the intraparenchymal space.⁴ Cell sorting or cell engineering to improve the targeted delivery needs to be further investigated. In addition, the success of targeted delivery also seems to be strongly dependent on the cell type used. Mononuclear cells of different origins, for instance, have shown very limited to no tropism to the ischemic brain tissue. It has also been postulated that cell size determines, in part, the safety profile of an intra-arterial delivery, whereas larger cell types might lead to microembolic obstruction of capillaries and strokes.^5–7 The mechanistic theories about transendothelial migration and the safety concerns have led to an additional important consideration, which is the monitoring of cell delivery. In vivo cerebral blood flow measurements⁸ and advanced magnetic resonance imaging (MRI)⁹ techniques to follow cell delivery in real time are being developed and should ideally be implemented in future clinical trials.

In this review, we will focus on the current knowledge related to the safety of intra-arterial cell delivery in stroke and will present novel methods that would allow monitoring of the cell delivery process. We will also put these preclinical concepts into a clinical perspective.

Safety of Intra-Arterial Injection After Stroke

Uninterrupted cerebral blood flow is critical for preserving the structure and function of the nervous tissue. Preserving blood circulation is of even greater importance in the aftermath of stroke, as homeostasis is fragile and any disturbance of nutrient/oxygen supply triggered by intra-arterial intervention may exacerbate the secondary damage. Cerebral capillaries are ≈5 to 10 μm in diameter and circulating cellular elements, including erythrocytes (7 μm) or leukocytes (6–18 μm), pass seamlessly through them. The adhesion of leukocytes and diapedesis occurs primarily at the site of postcapillary venules,¹⁰ so the trophic function of capillaries is maintained. Although some degree of temporary capillary blockage may be tolerated, if a critical threshold is exceeded, this inevitably leads to local hypoxia/ischemia and microembolic lesions. The density of cerebral capillaries varies in different brain structures, with the cortex having ≈5× the density of the corpus callosum,¹¹ and in this context, white matter might be more vulnerable to capillary occlusion. During intra-arterial stem cell delivery, relatively large numbers of cells are infused, with the anticipation that they will be captured by the cerebral vasculature; however, the cell load or local pressure disturbances may compromise the safety of this procedure.

To date, over 50 intra-arterial cell delivery studies in stroke have been published, and many studies have reported procedure-related complications. Important lessons on safety were learned, and several factors have been identified as critical for the safety of intra-arterial cell delivery. The most important variables that were identified are cell type and size, cell dose, infusion speed, and preservation of arterial blood flow in the feeding vessel during infusion. Other important factors to consider are timing after stroke onset and the anatomic considerations of the target (Figure 1). Comprehensive overview of the experimental conditions is included in Table I in the online-only Data Supplement. Details pertaining safety are included in Table II in the online-only Data Supplement.

Much more at link.