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A Google Earth Approach to Understanding Collagen Mineralization

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Unravelling the process of collagen mineralisation in our bones

Using stem cells and an innovative combination of microscopy techniques, researchers have advanced our understanding of this key structural protein.

Collagen is a vital component in bone. This long, fibrous protein organises in bundles and becomes mineralised, like reinforced concrete providing structure and support. And the hierarchical organisation of collagen into a matrix gives bone its impressive mechanical properties. “It’s tough, but it can bend a bit, you don’t break your leg when you hit a coffee table,” notes Nico Sommerdijk(opens in new window), professor in the Department of Medical BioSciences at Radboud University Medical Center. But as a very hierarchical material, collagen is different in any place, making it difficult for us to understand how it is built and composed. How collagen mineralisation happens is an even trickier question, which Sommerdijk and his team sought to answer through the COLMIN(opens in new window) project. COLMIN was funded by the European Research Council(opens in new window). “I wanted to go to a living system where I could see how the mineral and the collagen are produced and how they interact together,” says Sommerdijk, “what I call a ‘living in vitro system’.”

Creating a ‘mini-bone’ and a ‘bone-on-a-chip’

The COLMIN team created a bone-like piece of tissue as close as possible to the real thing at nanoscale in order to figure out the process of bone formation. The researchers encouraged stem cells to differentiate into bone-like cells, specifically like osteoblasts: the ones responsible for creating bone. They grew a ‘mini-bone’ organoid, smaller than 1.2 nanometres in length, a tissue similar to the disordered and flexible early bone. They could observe the tissue forming the extracellular matrix of collagen, before mineralisation happened. They investigated these processes using optical fluorescence microscopy. To then analyse the 3D structure, they devised a system able to keep the cells alive while imaging them, essentially creating a ‘bone-on-a-chip’.

Advances in microscopy techniques

In cryogenic electron microscopy, samples are frozen, which makes it difficult to find what you are looking for – like looking at just the top of a frozen lake, for something deep inside, adds Sommerdijk. So one member of the project devised a unique sample holder able to imprint a pattern into the sample before it is frozen – essentially providing a map, which they could use to explore the 3D structure. Then they adopted another technique known as Raman microscopy to explore the chemical information in the bone. The team decided to demineralise a piece of human bone, and – combining their imaging techniques – could watch it remineralise. They were able to visualise different types of mineralisation in bone samples from patients with brittle bone disease, a rare affliction in which collagen is overmodified as it is produced, creating chaotic bone formation.

Understanding brittle bone disease

“We now have a very detailed follow-up study in which we show that this over-modification, which happens only in a few places, has big effects on how the collagen is able to get itself into this very highly organised structure,” Sommerdijk explains. Another major advance was to examine how a protein known as fetuin, which may carry minerals to bones – travels around the body into cells. “We actually could see for the first time a biological process in a liquid phase electron microscope,” notes Sommerdijk. The project’s findings will help set a benchmark for advanced analysis of bone formation and help us understand this complex process further.

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