Article by Roberta Lock & Richard Z. Zhuang
Recreating the Human Bone Marrow "On-a-Chip"
Organ-on-a-chip model of vascularized human bone marrow niches, Biomaterials, 2022
Drew E.Glaser et al., Steven C. George Lab
Bone marrow is the body's blood cell factory: From the red blood cells that carry oxygen, the white blood cells that fight off diseases, to the platelets that clot blood after injury, our blood needs a continuous supply of cells from the bone marrow to keep us healthy. Creating a lab-grown model of the human bone marrow is important to understanding how it functions. However, doing so is a major challenge. Our bone marrow is composed of various cell types and different microenvironments that we call "niches". Creating a model that is complex enough to capture human biology, but still simple enough to make, control, and study is a difficult balance to manage. This research shows a way to model human bone marrow in the lab that allows us to study how it functions with with precise spatial and temporal resolution.
What did the researchers do?
Using microfluidic and stem cell technologies, researchers developed a vascularized 3D model of the human bone marrow that consisted of both of the two bone marrow niches. To demonstrate its healthy functionality, they showed that the model: maintains bone marrow with distinct niche-specific properties, displays bone marrow-specific properties in the vasculature, and supports hematopoietic (blood-generating) stem/progenitor cells . An important part of engineered tissues is not only how it mimics healthy function but also in response to drugs and disease. Using this model, the researchers were able to visualize how cancer cells can migrate into the bone marrow. The researchers also tested two drugs used in cancer treatment that affect white blood cell production and showed that their engineered bone marrow responds to drugs in a way consistent with what is expected in the body.
Immunofluorescence of Engineered Bone Marrow by S. George Lab
Why is this important?
The bone marrow is composed of several distinct niches that are small and close together. Currently, understanding of these niches and niche-specific functions has been gained by studying the bone marrow in small animal models. However, animals do not necessarily represent the bone marrow function in humans. This model is created using human cells, is much simpler, but still recreates the main functions and characteristics of human bone marrow under tightly controlled conditions. Importantly, this allows for studying individual niches and while closely monitoring their function under different conditions, including how they act in isolation, in proximity with other niches, and under different sources of stress (e.g. - diseased or drug induced), enabling better understanding of how our bone marrow works.
How did they achieve this?
The microfluidic device setup (shown above) enables the two hexagonal chambers to be mostly separate, while still allowing for movement of signaling molecules and cells in between. Endothelial cells (blood vessel cells) and a stromal (supporting) cells specific to each niche are mixed and suspended in a hydrogel, then loaded into their respective hexagonal chambers. Over 4-7 days, endothelial cells self organize into vascular networks. By day 14, the engineered bone marrows are ready for experiments.
The microfluidic device also consisted of a third chamber at the bottom that allows for an additional cell type if necessary. This was used to introduce cancer cells for modelling of cancer cell invasion into the bone marrow niches in one of the experiments.
What comes next?
Further characterization. The researchers were able to show that their engineered bone marrow closely resembles basic properties and functions of the human bone marrow in many ways. It important to know just how accurate the model is and also where it may fall short. The microenvironments can be cultured for longer periods of time to see if the model supports the blood cell population formation and maintenance for longer time points. It can be more thoroughly tested with other stressors to see how close the model's response is to the response of natural bone marrow found in the body.
Further exploration. There are several ways to use this model to further explore the bone marrow niches and their responses to different conditions. The researchers briefly looked into how it responds to drug and showed infiltration of cancer cells. These studies are great proof-of-concepts that open the door to more detailed investigations. We can use this models to look into how cancer infiltrates the bone marrow over time and understand the mechanisms of communication between the bone marrow and the cancer cells.
How simple is too simple? Organ-on-a-chip models must carefully balance simplicity of the model with physiological relevance (meaning it must mimic the body’s function enough to be a useful model). There are several features of the bone marrow microenvironment that are missing from this model that might significantly impact cell function, including the mineralized bone and nerve components. Future designs of this model may experiment with adding features like this to increase the complexity and physiological relevance of the model.