Abstract
Cell therapies for neonatal morbidities are progressing to early phase clinical trials. However, protocols for intravenous (IV) delivery of cell therapies to infants have not been evaluated. It has been assumed the cell dose prescribed is the dose delivered. Early in our clinical trial of human amnion epithelial cells (hAECs), we observed cells settling in the syringe and IV tubing used to deliver the suspension. The effect on dose delivery was unknown. We aimed to quantify this observation and determine an optimal protocol for IV delivery of hAECs to extremely preterm infants. A standard pediatric infusion protocol was modeled in the laboratory. A syringe pump delivered the hAEC suspension over 60 minutes via a pediatric blood transfusion set (200‐μm filter and 2.2 mL IV line). The infusion protocol was varied by agitation methods, IV‐line volumes (0.2‐2.2 mL), albumin concentrations (2% vs 4%), and syringe orientations (horizontal vs vertical) to assess whether these variables influenced the dose delivered. The influence of flow rate (3‐15 mL/h) was assessed after other variables were optimized. The standard infusion protocol delivered 17.6% ± 9% of the intended hAEC dose. Increasing albumin concentration to 4%, positioning the syringe and IV line vertically, and decreasing IV‐line volume to 0.6 mL delivered 99.7% ± 13% of the intended hAEC dose. Flow rate did not affect dose delivery. Cell therapy infusion protocols must be considered. We describe the refinement of a cell infusion protocol that delivers intended cell doses and could form the basis of future neonatal cell delivery protocols.
Highlights
Promising preclinical advances in regenerative cell therapies for major neonatal morbidities including bronchopulmonary dysplasia (BPD) and brain injury have led to early phase clinical trials.[1,2,3,4,5,6,7,8]
The human amnion epithelial cells (hAECs) density of aliquots 3 and 4 was less than 10% of the starting density. hAECs accumulated in the IV line such that the cell density in the IV-line postinfusion was 163% ± 21% of the starting hAEC density resulting in 27.5% ± 9% of the intended dose remaining in the IV line (Figure 2)
With decreasing IV-line volume, the hAEC dose delivered progressively increased from 30.3% ± 10.0% for a 2.2 mL line, 46.3% ± 4.7% for a 1.2 mL line, and 55.3% ± 14.4% for a 0.6 mL line, to 88.1% ± 15.0% for a 0.2 mL line (P < .0001; Figure 3B)
Summary
Promising preclinical advances in regenerative cell therapies for major neonatal morbidities including bronchopulmonary dysplasia (BPD) and brain injury have led to early phase clinical trials.[1,2,3,4,5,6,7,8] As feasibility and early safety reports emerge, the challenges of translation have been widely documented.[6,9,10] one challenge has been overlooked—the reliable delivery of a known dose of cells. It has been assumed that the intended dose of cells is the dose delivered. Such an assumption is fundamental to the validity and interpretation of early phase safety studies and of future efficacy trials.
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