The number of clinical trials using mesenchymal stem cells (MSCs) has increased since 2008, but this trend slowed in the past several years and dropped precipitously in 2018. Previous reports have analyzed MSC clinical trials by disease, phase, cell source, country of origin, and trial initiation date, all of which can be downloaded directly from ClinicalTrials.gov. We have extended analyses to a larger group of 914 MSC trials reported through 2018. To search for potential factors that may influence the design of new trials, we extracted data on routes of administration and dosing from individual ClinicalTrials.gov records as this information cannot be downloaded directly from the database. Intravenous (IV) injection is the most common, least invasive and most reproducible method, accounting for 43% of all trials. The median dose for IV delivery is 100 million MSCs/patient/dose. Analysis of all trials using IV injection that reported positive outcomes indicated minimal effective doses (MEDs) ranging from 70 to 190 million MSCs/patient/dose in 14/16 trials with the other two trials administering much higher doses of at least 900 million cells. Doseresponse data showing differential efficacy for improved outcomes were reported in only four trials, which indicated a narrower MED range of 100-150 million MSCs/ patient with lower and higher IV doses being less effective. The results suggest that it may be critical to determine MEDs in early trials before proceeding with large clinical trials.

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Cell encapsulation in alginate prevents migration and extends cell survival in vivo while allowing the secretion of factors across semipermeable capsules. Confocal microscopy is used to measure numbers of cells/capsule, but is time-consuming and limited to capsule diameters <0.4 mm for accurate counting. A rapid, accurate and inexpensive method for measuring the number of cells per capsule by using 50 mM ethylenediaminetetraacetic acid to collapse capsules into a single plane was developed. This assay was used to accurately count the number of live cells/capsule for capsules crosslinked with 50 mM BaCl2 with diameters up to 0.8 mm. This assay is ideal for counting cells/capsule during optimization to scale up the production of encapsulated cells, and for determining dosing in translational studies.