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A new organ-on-a-chip, mimicking human bone marrow, enabled the investigation of damage to the marrow caused by radiation and drugs. The device, developed in Boston by an academia–industry collaboration, also correctly predicted the mechanism of a rare genetic disease (Nat. Biomed. Eng. 10.1038/s41551-019-0495-z).
The bone marrow generates billions of blood cells every day and is therefore affected by cancer treatments that work by disrupting cell growth, such as chemotherapy and radiation. This can cause anaemia, bleeding and a high risk of infection.
Until David Chou, Viktoras Frismantas and their colleagues developed the bone marrow chip, the only way to study living marrow tissue effectively was to take painful biopsies from the bones. Other methods to study bone marrow in the laboratory or in animals did not reproduce effects seen in patients.
“The ability to efficiently use human cells rather than animal models offers numerous benefits, both in terms of translatability to the clinic and reduction of animal usage,” says Stefan Platz from AstraZeneca, which co-funded this research and hopes to use the chip for their drug development.
Anatomy of the chip
The bone marrow chip is the size of a USB memory stick and made of clear silicone rubber, with two parallel channels separated by a membrane. The top channel is filled with bone marrow progenitor cells from the patient and stromal cells embedded in a matrix gel to mimic the 3D nature of marrow tissue. The lower channel is lined with endothelial cells to mimic the blood vessels. A liquid medium that supports the growth and differentiation of bone marrow cells into different blood cell types flows through the lower channel to feed the cells and remove waste, thereby mimicking blood flow.
Compared with marrow cells grown in suspension or gel cultures, the chip improved the long-term survival of bone marrow progenitor cells and supported their growth and differentiation into white and red blood cells. Some neutrophils even migrated from the marrow channel into the lower channel (the “blood vessel”). This behaviour is equivalent to cells living in real bone marrow.
The researchers, from the Wyss Institute at Harvard University, then exposed the chip to a chemotherapy drug and found that it was damaged at the same drug concentrations that cause damage in patients.
To see whether the chip could also be used to predict the effect of new chemotherapy drugs, Chou and his team tested a drug that is currently in development by AstraZeneca. Because of the continuous flow through the lower channel on the chip, they were able to recreate the dynamic changes in drug levels observed in blood when the drug was administered to patients in a clinical trial.
Exposure to the drug for a short time caused a decrease in red and white blood cells, while treatment with the same total amount of drug administered over a longer time surprisingly only caused a drop in white blood cells. The effects observed on the chip matched those in the trial participants and even offered a way to study this effect further.
When testing radiation damage, once again the chip displayed toxicity at the expected radiation doses.
A doorway to the study of rare genetic diseases
The leader of the research team, Donald Ingber, says: “With this model in hand that can also replicate patient-specific marrow responses, we are in a position to assist in the design of human clinical trials for rare genetic disorders and advance personalized medicine in ways not possible before.”
A first glance at this potential was provided by the investigation of Shwachman-Diamond Syndrome, a rare genetic disease resulting in bone marrow failure with abnormally low counts of white blood cells. Animal models failed to reproduce this disease. However, applying cells from affected patients to the bone marrow chip precisely replicated the phenotype. This allowed the researchers to discover a previously unknown role for the CD13 protein in this process.
In the future, the team wants to evaluate whether the chip can be used to develop well-tolerated dosing regimens for cancer treatment and develop therapies for bone marrow recovery using the novel organ-on-a-chip.