. 2020 Dec 14;12:575990. doi: 10.3389/fnagi.2020.575990

Table 2.

Routes of administration of completed stem cell trials for ischemic stroke.

Intravenous (IV)	Intra-arterial (IA)	Intracranial (IC)	Intrathecal	Intranasal
Bang et al. (2005); Lee et al. (2010); Bhasin et al. (2011); Honmou et al. (2011); Savitz et al. (2011); Chen et al. (2013); Prasad et al. (2014); Qiao et al. (2014); Taguchi et al. (2015); Hess et al. (2017); Laskowitz et al. (2018); Fang et al. (2019) and Levy et al. (2019)	Barbosa da Fonseca et al. (2010); Friedrich et al. (2012); Moniche et al. (2012); Banerjee et al. (2014) and Savitz et al. (2019)	Kondziolka et al. (2000, 2005); Savitz et al. (2005); Suarez-Monteagudo et al. (2009); Chen et al. (2013, 2014); Kalladka et al. (2016); Steinberg et al. (2016, 2018) and Muir et al. (2020)	Chen et al. (2013) and Sharma et al. (2014)
Systemic administration Advantage: • Simple procedure/ease of delivery Disadvantages: • Poor biodistribution to the brain: 0.9% after 24 h (Rosado-de-Castro et al., 2013) • Reperfusion of lesion after cell delivery not confirmed	Systemic administration Advantage: • When infused into the internal carotid or middle cerebral arteries, cell delivery to the brain occurs before other organs Disadvantages: • Reperfusion of lesion after cell delivery not confirmed • Lowest biodistribution to the brain overall: 0.6% after 24 h (Rosado-de-Castro et al., 2013) • Potential for complications and/or thrombosis	Local administration Advantage: • Greatest cell retention at lesion site compared to intra-arterial or intravenous: in mouse studies, 60% IC (compared to ∼1.5% IV) after 3 days (Barish et al., 2017) Disadvantages: • Uneven cell distribution throughout the lesion (Li et al., 2000; Giraldi-Guimardes et al., 2009) • An invasive procedure, requiring sedation and stereotactic localization	Local administration Advantages: • Direct access to CSF circulation throughout the brain and spinal cord • Less complex procedure than intracranial Disadvantage: • The mechanism of cellular migration from CSF space into brain parenchyma remains unknown	Local administration Advantages: • Enhanced blood-brain barrier permeability • Ease of delivery Disadvantage: • Unproven: clinical trials are ongoing and no data has been published to date

Intravenous (IV)

Intra-arterial (IA)

Intracranial (IC)

Intrathecal

Intranasal

Bang et al. (2005); Lee et al. (2010); Bhasin et al. (2011); Honmou et al. (2011); Savitz et al. (2011); Chen et al. (2013); Prasad et al. (2014); Qiao et al. (2014); Taguchi et al. (2015); Hess et al. (2017); Laskowitz et al. (2018); Fang et al. (2019) and Levy et al. (2019)

Barbosa da Fonseca et al. (2010); Friedrich et al. (2012); Moniche et al. (2012); Banerjee et al. (2014) and Savitz et al. (2019)

Kondziolka et al. (2000, 2005); Savitz et al. (2005); Suarez-Monteagudo et al. (2009); Chen et al. (2013, 2014); Kalladka et al. (2016); Steinberg et al. (2016, 2018) and Muir et al. (2020)

Chen et al. (2013) and Sharma et al. (2014)

Systemic administration
Advantage:

•
Simple procedure/ease of delivery

Disadvantages:

•
Poor biodistribution to the brain: 0.9% after 24 h (Rosado-de-Castro et al., 2013)

•
Reperfusion of lesion after cell delivery not confirmed

Systemic administration
Advantage:

•
When infused into the internal carotid or middle cerebral arteries, cell delivery to the brain occurs before other organs

Disadvantages:

•
Reperfusion of lesion after cell delivery not confirmed

•
Lowest biodistribution to the brain overall: 0.6% after 24 h (Rosado-de-Castro et al., 2013)

•
Potential for complications and/or thrombosis

Local administration
Advantage:

•
Greatest cell retention at lesion site compared to intra-arterial or intravenous: in mouse studies, 60% IC (compared to ∼1.5% IV) after 3 days (Barish et al., 2017)

Disadvantages:

•
Uneven cell distribution throughout the lesion

(Li et al., 2000; Giraldi-Guimardes et al., 2009)

•
An invasive procedure, requiring sedation and stereotactic localization

Local administration
Advantages:

•
Direct access to CSF circulation throughout the brain and spinal cord

•
Less complex procedure than intracranial

Disadvantage:

•
The mechanism of cellular migration from CSF space into brain parenchyma remains unknown

Local administration
Advantages:

•
Enhanced blood-brain barrier permeability

•
Ease of delivery

Disadvantage:

•
Unproven: clinical trials are ongoing and no data has been published to date

Shading = in pending clinical trials only (no results published).