‘Bone in a dish’ opens new window on cancer initiation, metastasis and bone healing

‘Bone in a dish’ opens new window on cancer initiation, metastasis and bone healing

Material developed at OHSU has a 3D mineral structure populated with living cells, providing a unique model to study bone function

Researchers in Oregon have engineered a material that replicates human bone tissue with an unprecedented level of precision, from its microscopic crystal structure to its biological activity. They are using it to explore fundamental disease processes, such as the origin of metastatic tumours in bone, and as a treatment for bone injuries.

“Essentially it is a miniaturised bone in a dish that we can produce in a matter of 72 hours or less,” says biomedical engineer Luiz Bertassoni, assistant professor in the Oregon Health and Science University (OHSU) School of Dentistry and a member of the Cancer Early Detection Advanced Research Center.

Like real bone, the material has a 3D mineral structure populated with bone cells, nerve cells and endothelial cells that self-organize into functioning blood vessels.

“Researchers in our field have become used to cultivating cells within a protein mixture to approximate how cells live in the body. But this is the first time anyone has been able to embed cells in minerals, which is what characterises the bone tissue,” Bertassoni says.  

And that’s what makes the new material promising as a model to study bone function, diseases, and bone regeneration. “With this model system, you can start asking questions about how bone cells attract different types of cancers, how cancer cells move into bone, how bone takes part in the regulation of marrow function,” says Bertassoni, who published the results in the journal Nature Communications.

“Being able to engineer truly bone-like tissues in the lab can also be transformative for regenerative medicine,” Bertassoni says, “Since the current treatment for large bone fractures requires the removal of the patient’s own healthy bone so that it can be implanted at the site of injury. We can reproduce the architecture of bone down to a nanometer scale.”

The recipe starts with the mixing of human stem cells into a solution loaded with collagen, a protein abundant in the matrix of bone tissue. The collagen proteins link together, forming a gel embedded with the stem cells. The researchers then flood the gel with a mixture of dissolved calcium and phosphate, the minerals of bone. They then add the protein osteopontin derived from cow milk, to keep the minerals from forming crystals too quickly. This additive, which clings to calcium and phosphate minimizes the minerals’ toxicity to cells.

The mixture diffuses through a network of channels about the width of a strand of DNA in the spongy collagen, and the dissolved minerals precipitate into orderly layers of crystals.

“We can reproduce the architecture of bone down to a nanometer scale,” says Bertassoni. “Our model goes through the same biophysical process of formation that bone does.”

In this calcified environment, stem cells develop into functioning bone cells, osteoblasts and osteocytes without the addition of any other molecules, as if they knew they were being embedded in an actual bone matrix. Within days, the growing cells squeeze slender protrusions through spaces in their mineralised surroundings to connect and communicate with neighbouring cells. The bone-like engineered structure creates a microenvironment that is sufficient to cue stem cells that it’s time to mature into bone cells.

Nerve cells added to the mixture formed interconnected networks that persisted after mineralisation. Endothelial cells, likewise, formed networks of tubes that remained opened after mineralisation.

To test the usefulness of the material as a disease model, the researchers implanted their engineered bone beneath the skin of laboratory mice. After a few days, the lab-made blood vessels had connected with the vasculature in the mouse bodies. When the researchers injected prostate cancer cells nearby, they found that tumour growth was three times higher in the mice given mineralised bone constructs than in those with the non-mineralised controls.

Source: Oregon Health and Science University

Reference: https://doi.org/10.1038/s41467-019-11455-8

Picture caption: Luiz Bertassoni shows an engineered material that replicates human bone tissue. (Source: OHSU/Joe Rojas-Burke)

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