̽��ֱ�� of Cambridge - Richard Farndale

Patching up a broken heart

lw355 — Fri, 16 Jun 2017 15:00:54 +0000

When the body’s repair system kicks in, in an attempt to remove the dead heart cells, a thick layer of scar tissue begins to form. While this damage limitation process is vital to keep the heart pumping and the blood moving, the patient’s problems have really only just begun.

Cardiac scar tissue is different to the rest of the heart. It doesn’t contract or pump because it doesn’t contain any new heart muscle cells. Those that are lost at the time of the heart attack never come back. This loss of function weakens the heart and, depending on the size of the damaged area, affects both the patient’s quality of life and lifespan.

“In many patients, not only is their heart left much weaker than normal but they are unable to increase the amount of blood pumped around the body when needed during exercise,” explains Dr Sanjay Sinha. “I’ve just walked up a flight of stairs… it’s something I take for granted but many patients who’ve survived heart attacks struggle to do even basic things, like getting dressed. While there are treatments that improve the symptoms of heart failure, and some even improve survival to a limited extent, none of them tackles the underlying cause – the loss of up to a billion heart cells.”

̽��ֱ��numbers are stark. “Half a million people have heart failure in the UK. Almost half of them will not be alive in five years because of the damage to their heart. At present, the only way to really improve their heart function is to give them a heart transplant. There are only 200 heart transplants a year in the UK – it’s a drop in the ocean when many thousands need them.”

Sinha wants to mend these hearts so that they work again. “Not just by a few percent improvement but by a hundred percent.”

He leads a team of stem cell biologists in the Cambridge Stem Cell Institute. Over the past five years, with funding from the British Heart Foundation, they have been working with materials scientists Professors Ruth Cameron and Serena Best and biochemist Professor Richard Farndale on an innovative technique for growing heart patches in the laboratory – with the aim of using these to repair weakened cardiac tissue.

“In the past, people have tried injecting cardiomyocytes into damaged hearts in animal models and shown that they can restore some of the muscle that’s been lost,” says Sinha. “But even in the best possible hands, ninety percent of the cells you inject are lost because of the hostile environment.”

Instead, the Cambridge researchers are building tiny beating pieces of heart tissue in Petri dishes. ̽��ֱ��innovation that makes this possible is a scaffold. “ ̽��ֱ��idea is to make a home for heart cells that really suits them to the ground. So they can survive and thrive and function.”

̽��ֱ��scaffold is made of collagen – a highly abundant protein in the animal kingdom. Best and Cameron are experts at creating complex collagen-based structures for a variety of cell types – bone marrow, breast cancer, musculoskeletal – both as implants and as model systems to test new therapeutics.

“ ̽��ֱ��technology we’ve developed for culturing cells is exciting because it is adaptable to a huge range of applications – almost any situation where you’re trying to regenerate new tissue,” explains Best.

Best and Cameron use ‘ice-templating’ to build the scaffold. They freeze a solution of collagen, water and certain biological molecules. When the water crystals form, they push the other molecules to their boundaries. So, when the crystals are vapourised (by dropping the pressure to low levels), what’s left is a complex three-dimensional warren.

“We have immense control over this structure,” adds Cameron. “We can vary the pore structure to make cells align in certain orientations and control the ratios of cell types. We are building communities of millions of cells in an environment that resembles the heart.”

Cardiomyocytes fare better when they are surrounded by other cell types and have something to hold on to. They use proteins on their surface called integrins to touch, stick to and communicate with their environment. Farndale has perfected a ‘toolkit’ that pinpoints exactly which parts of collagen the integrins bind best; he then makes matching peptide fragments to ‘decorate’ the collagen scaffold. This gives cells a foothold in the scaffold and encourages different cell types to move in and populate the structure.

“We don’t just want a cardiac scaffold – we want it to have blood vessels and the same mechanical properties as the heart,” explains Sinha. “If it’s going to contract and function efficiently, it needs a really good blood supply. And the whole three-dimensional structure must be strong enough to survive the hostile environment of a damaged heart.”

Meanwhile, Sinha’s team pioneered the production of the different cell types needed for the patch. Their starting material is human embryonic stem cells, but they have also taken adult human cells and ‘reset’ their developmental clock. “In theory this means we can take a patient’s own cells and make patches that are identical to their own tissue. That said, millions of people are going to need this sort of therapy and so our focus at the moment is on coming up with a system where a small number of patches might be available ‘off the shelf’, with patients receiving the nearest match.

̽��ֱ��team is completing tests on the ideal combination of scaffold structure, peptide decoration and mix of cells to create a beating vascularised tissue. Next, the researchers will work with Dr Thomas Krieg in the Department of Medicine to graft the tissue into a rat heart. Their aim is to show that the patch makes vascular connections, integrates mechanically and electrically with heart muscle, and contracts in synchrony with the rest of the heart. Once they’ve accomplished this, they will scale up the size of the patches for future use in people.

“It’s exciting,” says Sinha. “We are recreating a tissue that has all the components we see in an organ, where the cells start talking together in mysterious and wonderful ways, and they start to work together as they do in the body. Our vision is that this technology will bring hope to the millions of patients worldwide who are suffering from heart failure, and allow them to lead a normal life again.”

It is almost impossible for an injured heart to fully mend itself. Within minutes of being deprived of oxygen – as happens during a heart attack when arteries to the heart are blocked – the heart’s muscle cells start to die. Sanjay Sinha wants to mend these hearts so that they work again.

We are recreating a tissue that has all the components we see in an organ, where the cells start talking together in mysterious and wonderful ways, and they start to work together as they do in the body.

Sanjay Sinha

̽��ֱ��District and Jonathan Settle

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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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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