On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology

Abstract

The inaccessibility of living bone marrow hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human bone-marrow-on-a-chip supports the differentiation and maturation of multiple blood-cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of marrow injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation as well as marrow recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34 + cells and bone-marrow-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that bone-marrow chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil-maturation abnormality. As an in vitro model of haematopoietic dysfunction, the bone-marrow-on-a-chip may serve as a human-specific alternative to animal testing for the study of bone-marrow pathophysiology.

Is it Time for Reviewer 3 to Request Human Organ Chip Experiments Instead of Animal Validation Studies?

“…The presence of dynamic fluid flow, tissue-tissue interfaces, and physiological mechanical cues enhances the fidelity of cell differentiation and increases expression of tissue-specific functionalities on-chip relative to conventional cultures, static MPS, and even organoids. [14,18,23,26,27,33,36,44,46,71] Tissues in Organ Chips also can be probed using virtually any type of analytic technique that is used in other in vitro models or animal studies, including methods leveraging high resolution microscopy, flow cytometry, transcriptomics, proteomics, metabolomics, and histological analysis, and as recently demonstrated, automated high content confocal imaging with fluorescent reporters. [72] In addition, because Organ Chips can be instrumented with in-line electrical, chemical, mechanical, and optical sensors (both alone and in combination), they can incorporate real-time readouts and enable probes of critical cell and tissue functions, including tissue Figure 7.…”

Hematopoietic progenitors polarize in contact with bone marrow stromal cells by engaging CXCR4 receptors

“…By contrast, in the peri-vascular niches, close to blood veins and arteries, endothelial cells and pericytes stimulate HSPC proliferation and differentiation (Kopp et al, 2005) (Kiel et al, 2005) (Ding et al, 2012) (Greenbaum et al, 2013) (Asada et al, 2017). To investigate the molecular and cellular mechanisms underlying these activities, we designed a microfluidic bone-marrow on a chip model of the HPSC niche (Ingavle et al, 2019) (Chou et al, 2020) (Sieber et al, 2018). The model was inspired by the pioneering work of Noo-Li Jeon, who described the set-up for the micro-channel geometry and the culture conditions necessary for inducing endothelial cells self-organization into hollow and perfusable 3D networks (Kim et al, 2013).…”

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

“…This indicates that the technology offered is still in development and not in its final form: only in the last couple of years, the emerging OOAC companies have established partnerships and collaborative relationships with pharmaceutical companies to accelerate the development of OOAC technology and testing [27]. Peer-reviewed publications of analytical results from these operational environments have reported the first successful applications in operational conditions (TRL 7) and confirmed the potential for OOAC to improve the process for predictions of adverse drug reactions before drug candidates enter clinical trials [131,132].…”