̽��ֱ�� of Cambridge - collagen

Body builders: collagen scaffolds

lw355 — Wed, 04 Jun 2014 09:07:30 +0000

It may not look like much to the naked eye, but collagen is remarkably strong. ̽��ֱ��most abundant protein in the animal kingdom, it gives strength and structure to skin, tendons, ligaments, smooth muscle tissue and many other parts of the body.

Through precise manipulation at a structural level, collagen can also be used as a construction material in the laboratory or clinic to help regenerate new tissue, repair damaged cartilage and bone, or aid in the development of new therapies for cardiac disease, blood disorders and cancer.

To understand these conditions better and develop new treatments, or regenerate new tissue, researchers require models that very closely mimic the complex, three-dimensional environments found in human tissue.

As a natural material, collagen is ideal for these biomimetic applications. By shaping it into porous structures, collagen acts as a ‘scaffold’ on which cells and tissue can grow in three dimensions in predetermined forms, mimicking those found in the body.

̽��ֱ��idea of using collagen as a scaffold is not new, but the very high level of control that Cambridge researchers are able to achieve over its properties has made a huge range of clinical applications possible, including the repair of damaged joints or tissue, or accelerating the development of new therapies for cancer.

“There is an increasing need for improved materials that work with the systems in the body to regenerate healthy tissue, rather than just replacing what’s there with something synthetic,” said Professor Ruth Cameron of the Department of Materials Science and Metallurgy, who, along with Professor Serena Best, is working with researchers from across the ̽��ֱ�� to develop the scaffolds for a range of clinical applications. “You’re trying to help the body to heal itself and produce what it needs in order to do that.”

To build the scaffolds, the researchers begin with a solution of collagen and water and freeze it, creating ice crystals. As the collagen cannot incorporate into ice, it gathers around the edges of the crystals. When the pressure around the ice is dropped to very low levels, it converts directly from a solid to vapour, leaving the collagen structure behind. By precisely controlling how the ice crystals grow as the water freezes, the researchers are able to control the shape and properties of the resulting collagen scaffold.

By adding small groups of amino acids known as peptide sequences to the surface of the scaffold at different points, the way in which the collagen interacts with the growing cells changes, altering the potential uses for the scaffold. ̽��ֱ��peptide sequences signal certain cells to bind to the scaffold or to each other, while signalling other cells to migrate. Collectively, these signals direct the scaffold to form a certain type of tissue or have a certain type of biological response.

“ ̽��ֱ��scaffolds are a three-dimensional blank canvas – they can then be used in any number of different ways,” said Cameron, who is funded by the European Research Council. “They can be used to mimic the way in which natural tissue behaves, or they can be directed to form different sized or sequenced structures.”

̽��ֱ��technology has already gone from the laboratory all the way to patients, first as Chondromimetic, a product for the repair of damaged knee joints and bone defects associated with conditions such as osteoarthritis, trauma or surgery. By adding calcium and phosphate to the scaffold to mimic the structure of bone, it helps regenerate bone and cartilage. Chondromimetic has been through clinical trials and has received its CE mark, enabling its sale in Europe.

In future, the scaffolds could also see use as a treatment for cardiac disease. Working with Professor Richard Farndale from the Department of Biochemistry and Dr Sanjay Sinha from the Department of Medicine, and supported by funding from the British Heart Foundation, Best and Cameron are developing the scaffolds for use as patches to repair the heart after a heart attack.

Heart attacks occur when there is an interruption of blood to the heart, killing heart muscle. ̽��ֱ��remaining heart muscle then has to work harder to pump blood around the body, which can lead to a thickening of the heart wall and potential future heart failure.

By modifying the collagen scaffolds with the addition of peptide sequences, they could be used to grow new heart cells to ‘patch’ over areas of dead muscle, regenerating the heart and helping it function normally. Cells could be taken directly from the patient and reprogrammed to form heart cells through stem cell techniques.

While the work is still in its early stages, the scaffolds could one day be an important tool in treating coronary heart disease, which is the UK’s biggest killer. “These scaffolds give cells a foothold,” said Farndale, who is working with Sinha to characterise the scaffolds so that they encourage heart cells to grow. “Eventually, we hope to be able to use them, along with cells we’ve taken directly from the patient, to enable the heart to heal itself following cardiac failure.”

Another potentially important application for the scaffolds is in breast cancer research. By using them to grow mimics of breast tissue, the scaffolds could help accelerate the development of new therapies. Working with Professor Christine Watson in the Department of Pathology, Best and Cameron are fine-tuning the scaffolds so that they can be used to create three-dimensional models of breast tissue. If successful, this artificial breast tissue could assist with the screening of new drugs for breast cancer, reduce the number of animals used in cancer research and ultimately lead to personalised therapies.

“This is a unique culture system,” said Watson. “We are able to add different types of cells to the scaffold at different times, which no-one else can do. Better models will make our work as cancer researchers much easier, which will ultimately benefit patients.”

Like breast tissue, blood platelets also require a very specific environment to grow. Dr Cedric Ghevaert of the Department of Haematology is working with Best and Cameron to use the scaffold technology to create a bone-like niche to grow bone marrow cells, or megakaryocytes, for the production of blood platelets from adult stem cells. In theory, this could be used to produce platelets as and when they are needed, without having to rely on blood donations.

“ ̽��ֱ��technology for culturing the cells is actually quite generic, so the range of applications it could be used for in future is quite broad,” said Best. “In terms of clinical applications, it could be used in almost any situation where you’re trying to regenerate tissue.”

“In some senses, it can be used for anything,” added Cameron. “As you start to create highly organised structures made up of many different types of cells – such as the liver or pancreas – there is an ever-increasing complexity. But the potential of this technology is huge. It could make a huge difference for researchers and patients alike.”

Miniature scaffolds made from collagen – the ‘glue’ that holds our bodies together – are being used to heal damaged joints, and could be used to develop new cancer therapies or help repair the heart after a heart attack.

We are able to add different types of cells to the scaffold at different times, which no-one else can do

Christine Watson

Jennifer Ashworth

Collagen scaffold imaged using X-ray microtomography to reveal its 3D structure

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Collagen mechanics: learning from nature

bjb42 — Mon, 01 Sep 2008 15:37:11 +0000

Mention the word ‘biology’ and most people think immediately about cells. However, large portions of the human body are non-cellular and are made instead from an extracellular matrix (ECM) that provides much of the structural support around cells. This supportive function of the ECM is especially evident in the connective tissues of the body. Many load-bearing structures such as bones, teeth and ligaments are connective tissues and these have been the focus of recent bioengineering research in Cambridge.

Dr Michelle Oyen, Lecturer in the new Engineering for Life Sciences programme in the Department of Engineering, is studying the mechanical functions of connective tissues. Her research ranges from fundamental science and engineering projects through to collaborative projects with clinicians for developing mechanics-based tools for use in medical practice. ̽��ֱ��unifying theme of this research lies with the primary component of many connective tissues: the structural protein collagen.

Building blocks of natural materials

Collagen is ubiquitous; this triple-helical protein makes up a quarter of all proteins in the body. It self-assembles from the molecular scale up to large fibre-like structures, creating a hierarchical material with remarkable physical properties. Collagen combines with other ECM components – mainly water, non-collagenous proteins and sugars – and, in mineralised tissues, with bioceramics analogous to earth minerals. These non-living, but cell-derived, materials combine with cells to form living yet mechanically robust tissues.

Collagen takes on different roles in different parts of the body. In structural tissues, like bones and ligaments, it’s found in rope-like fibres that provide resistance to stretching and tearing forces. In cartilage, which is mostly loaded in compression, collagen has more of a ‘holding’ function, with the fibres arranged rather like a basket, retaining other hydrated proteins and sugars. In the lens of the eye, collagen is crystalline, organised precisely for optical transparency. In fact, there are over 20 different types of collagen in the body, and it is not even known precisely what functions they all fulfil.

Mechanics in medicine

̽��ֱ��study of the biomechanical properties of collagen and ECM is a particularly exciting and fast-growing field in reproductive medicine. One aspect of Dr Oyen’s research has been to examine the physical properties of the ECM in the amniotic sac, the membrane that ruptures (the ‘breaking of waters’), signalling imminent birth.

Rupture occurring before full-term gestation results in approximately a third of all premature births. Following the first-ever set of rigorous bioengineering studies on placental membranes, Dr Oyen and clinical colleagues at the ̽��ֱ�� of Minnesota concluded that the phenomenon is due to localised damage, not widespread overall membrane deterioration, and that diagnostic techniques may be developed to detect localised thinning and ECM damage for intervention into premature birth.

This project is taking a new direction since Dr Oyen’s arrival in Cambridge. By teaming up with researchers at the newly opened Centre for Trophoblast Research (www.trophoblast.cam.ac.uk), she will be able to examine placental development from an engineering and mechanics perspective.

Mimicking nature

Nature clearly creates dynamic, mechanically functional tissues that are different from anything engineers have made. As an example, cartilage, which forms the gliding surface that permits joint movement, is approximately 75% water and only 25% collagen, sugar and other proteins, and yet its stiffness and shock-absorbing capability make it comparable to solid rubber. Moreover, the cartilage-on-cartilage sliding interface has lower friction than ice sliding on ice.

In fact, when engineers design materials, uniformity and simplicity are often prized. Engineering materials do not always feature the multi-level hierarchical organisations found in protein-based materials, nor do they exemplify the dramatic spatial non-uniformity that has been found to strengthen natural materials. So, by learning from nature, novel engineering systems might be developed that utilise the principles found in natural materials – a field of technology that has been termed biomimetics.

In some instances, biomimetics takes the form of direct imitation, as in the case of a nanocomposite of mineral and proteins similar to natural bone. For cases of major bone defects, such as occurs through trauma or cancer, a bone-like material that is biocompatible can be seeded with cells to form a ‘tissue-engineered’ construct and implanted within the body. However, if you consider just how lightweight, yet stiff, strong and tough, a bone-like material is, why not use it for other structural applications such as architecture? This is a challenge that Dr Oyen is investigating.

To do this, you need to go back to first principles – how the material forms. With funding from the Royal Society, Dr Oyen is examining biomineralisation and the formation of mechanically robust bone-like materials. ̽��ֱ��work differs from tissue-engineering approaches in that there is no cellular component and the end applications are viewed as being remote from medicine. Although a large number of groups have considered the synthesis of biomimetic materials, far fewer have taken a primary angle associated with the measurement of mechanical properties. Dr Oyen views the materials as successful when they replicate both bone composition and mechanical behaviour.

Inspirational materials

It is also possible to abstract ideas from nature without directly imitating the materials themselves. As examples, key concepts that could guide the formation of ‘bone-inspired’ materials include: composite materials with a very large stiffness mismatch between the phases; materials that form from room-temperature deposition of a ceramic onto a self-assembled polymer; materials with up to seven different levels of hierarchical organisation; and materials that are self-healing. Each of these concepts could be applied to a system that is not protein based, and ongoing research both at Cambridge and across the world is incorporating these types of principles for materials development.

Compared with many branches of engineering, biomimetic engineering is comparatively new. In this rapidly expanding field, the lessons learnt from the physical and mechanical properties of natural materials such as collagen and bone offer great promise within an engineering framework. Not only is this sure to make a difference to 21st-century healthcare, but there are also ways in which engineering will itself benefit from the abstraction of ideas from nature.

For more information, please contact the author Dr Michelle Oyen (mlo29@cam.ac.uk)

at the Department of Engineering.

Because of their unique structure, biological tissues exhibit physical and mechanical properties that are unlike anything in the world of engineering.

So, by learning from nature, novel engineering systems might be developed that utilise the principles found in natural materials – a field of technology that has been termed biomimetics.

Dr Jon Heras, Equinox Graphics

collagen

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