Organ-On-A-Chip: Development and Clinical Prospects Toward Toxicity Assessment with an Emphasis on Bone Marrow

Abstract

Conventional approaches for toxicity evaluation of drugs and chemicals, such as animal tests, can be impractical due to the large experimental scale and the immunological differences between species. Organ-on-a-chip models have recently been recognized as a prominent alternative to conventional toxicity tests aiming to simulate the human in vivo physiology. This review focuses on the organ-on-a-chip applications for high-throughput screening of candidate drugs against toxicity, with a particular emphasis on bone-marrow-on-a-chip. Studies in which organ-on-a-chip models have been developed and utilized to maximize the efficiency and predictability in toxicity assessment are introduced. The potential of these devices to replace tests of acute systemic toxicity in animals, and the challenges that are inherent in simulating the human immune system are also discussed. As a promising approach to overcome the limitations, we further focus on an in-depth analysis of the development of bone-marrow-on-a-chip that is capable of simulating human immune responses against external stimuli due to the key roles of marrow in immune systems with hematopoietic activities. Owing to the complex interactions between hematopoietic stem cells and marrow microenvironments, precise control of both biochemical and physical niches that are critical in maintenance of hematopoiesis remains a key challenge. Thus, recently developed bone-marrow-on-a-chip models support immunogenicity and immunotoxicity testing in long-term cultivation with repeated antigen stimulation. In this review, we provide an overview of clinical studies that have been carried out on bone marrow transplants in patients with immune-related diseases and future aspects of clinical and pharmaceutical application of bone-marrow-on-a-chip.

Organ‐On‐A‐Chip Platforms: A Convergence of Advanced Materials, Cells, and Microscale Technologies

“…As such, new cell lines were developed that retained human relevance and the capacity to differentiate into any cell that makes up the human body without the ethical issues associated with their use. Extracting somatic cells (e.g., blood cells, testicular, keratinocytes, and pancreatic) from patients and reprograming them to human iPSCs enable researchers to fabricate patient specific platforms for drug discovery and disease modeling purposes . Some cell types can be directly reprogrammed into other lineages .…”

“…This tissue is responsible for continuously producing blood cells in our bodies via hematopoietic SCs . Hematopoietic SCs in bone marrow exist in a specific cell niche so that hematopoietic SCs maintain their phenotype and function . The bone marrow niche has been shown to be critical for self‐renewal and differentiation of hematopoietic SCs into blood cell lineage …”

Bone marrow-on-a-chip: Emulating the human bone marrow

“…In conclusion, the here presented bone marrow model demonstrates for the first time the successful long-term culture of functional multipotent HSCs in a dynamic environment. The model surpasses all previously presented 3D bone marrow models in culturing time of HSCs as well as in mimicking the in vivo environment (Kim et al, 2015). Predestining it as a model for sophisticated in vitro drug testing, thus, serving as an alternative to animal testing.…”

“…This construct was subsequently transferred to a microfluidic device and cultured for one week. (Kim et al, 2015; Torisawa et al, 2014). Unfortunately, no model was able to mimic the human hematopoietic stem cell niche meaning the continued sustainment of primitive HSCs while simultaneously allowing various hematopoietic populations to differentiate into their respective progeny.…”

Controlling Differentiation of Stem Cells for Developing Personalized Organ‐on‐Chip Platforms

“…Bone marrow is a sponge‐like, flexible, soft, incredibly complex tissue, with the responsibility of continuously producing blood and immune cells in the body . The bone‐marrow‐on‐a‐chip is beneficial to determine the effect of various chemical agents, drugs, and immune cells since the bone marrow plays a key role in immune system due to its hematopoietic activities.…”