Editors' ChoiceBioengineering

Microfluidic modeling of bone marrow pathophysiology

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Science Translational Medicine  19 Feb 2020:
Vol. 12, Issue 531, eaba9023
DOI: 10.1126/scitranslmed.aba9023

Abstract

Human bone-marrow-on-a-chip improves drug studies of hematopoietic cell function and identifies a neutrophil maturation defect in a genetic disorder.

Studying hematopoietic cell function is critical for improving outcomes in patients with rare blood disorders and for enhancing cell recovery in the bone marrow after drug- or radiation-induced toxicity that defines maximum tolerated dose. Hence, there is a strong interest in screening platforms that faithfully recapitulate bone marrow pathophysiology to speed drug development for rare genetic disorders and to predict bone marrow injury in the clinical setting.

Chou et al. developed a human microfluidics-based organ-on-chip system to study how bone marrow injury and a rare genetic disorder affect hematopoietic cell function. This three-dimensional (3D) multichannel system included a hematopoietic channel (seeded with human CD34+ and bone marrow stromal cells) interfacing with an endothelial channel (seeded with human endothelial cells) in which controlled fluid flow was established. Compared with static 3D or suspension culture conditions, the bone marrow chip improved cell proliferation and differentiation and more closely mimicked in vivo chemotherapy-induced cytotoxicity. Fluid flow in the endothelial channel allowed the authors to simulate different pharmacokinetic profiles and recapitulate two types of adverse effects, neutropenia and anemia, that were observed in phase I clinical trials with an Aurora B kinase inhibitor. The authors also showed that ionizing radiation exhibited dose-dependent toxicity on neutrophil and erythroid cells across multiple patient samples. Last, the bone marrow chip was used to model the hypoplastic phenotype in cells from patients with the rare genetic disorder Shwachman-Diamond syndrome and uncovered a neutrophil maturation defect.

The microfluidic bone marrow system developed by Chou et al. has great potential as a screening platform to study bone marrow pathophysiology and response to clinically relevant drug pharmacokinetic profiles and radiation exposures. Future studies need to investigate the use of autologous cells from a single patient, the differentiation of lymphoid cells, and integration with multiple organ systems. An important issue for studies using these types of microfluidics systems is the fabrication material (polydimethylsiloxane), which adsorbs small molecules and hence adds a confounding factor to interpreting the drug screening results. Human organs-on-chips hold great promise for accelerating drug development, improving toxicity prediction, and eventually personalizing therapies.

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