Materials that Impose Architecture within Stem Cell Populations

Copying natural development processes to create regenerative medicine products The human body develops from a single cell using specialised architectures built from molecules, materials and cells. By copying these developmental processes, Professor Kevin Shakesheff is beginning to create new therapies to stimulate tissue repair The human embryo

is a remarkable thing; it starts out as a single cell before dividing itself and, within a few weeks, becomes a complex system of cells and tissues that form the basic blueprint of our bodies. Our cells have an amazing ability to grow spontaneously and can self-assemble into incredibly complex tissue structures. Professor Kevin Shakesheff’s research aims to learn from the embryo, and his interest in its properties have opened up avenues of research that could change the way that patients who have suffered tissue damage are treated.

Professor Shakesheff is the principle investigator of the MASC project, based at the University of Nottingham. MASC, which stands for materials that impose architecture within stem-cell populations, aims to utilize breakthroughs in polymer science, nanotechnology, and materials processing, in order to create a new class of materials that could be used to mimic the regenerative nature of the human embryonic cell. “I’ve been interested in many years in the interaction between synthetic material and human cells,” Professor Shakesheff tells EU Research.

“The main application of this project is to try to use synthetic materials as scaffolds, within which human cells can form human tissue.”

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The project’s primary focus so far has been to look at possible clinical applications of using a synthetic material as a starting point for the growth of new tissue. The idea is that by using a synthetic, sponge-like material, new cells and blood vessels are encouraged to grow within the material’s porous structure. One potential application for this process would be for use with patients who have a large defect in their bone structure.

“You can place this material inside the patient’s bone,” Professor Shakesheff explains. “It would then allow local stem cells, already present within the patient in nearby tissues, to migrate to the structure and lay down new bone material.”

The next stage of the project will be to investigate how, by changing the three-

dimensional architecture of the scaffold, the way in which cells interact within the synthetic material can be changed and therefore encourage the growth of better quality tissue.

In order to achieve this, Professor Shakesheff and his team are looking at a number of methods. “One example,” he explains, “would be to embed within the synthetic material various drugs, which would encourage tissue formation at a faster rate; it would become a sort of pharmaceutical device.” Another method being explored is the introduction of outside stem cells to the structure. “Rather than relying on the patient having cells that migrate into the structure, you can put those cells in yourself; you would then know that there is a high concentration of the right cell type.”

Professor Shakesheff tells us that there is a large gap between what he and his team are accomplishing within a lab setting, and what the human embryo itself can achieve. “The MASC project is trying to bridge that gap by investigating what it is the human embryo can do in order to control how tissues form. We hope that by using the state of the art techniques that we are developing, we can develop this synthetic material that will have the same properties to control the growth of new tissue.”

EU Research

Professor Shakesheff explains that within the early stages of embryo formation, stem cells have not yet decided what they will develop into; within the tissue structure of the embryo, a growth factor is released, which is a protein based molecule. The growth factor migrates from a single point in three-dimensional space and creates a concentration gradient that affects all the cells at different levels. The combination of chemical gradients and local cell-tocell communication acts as a kind of postcode that tells the cells what kind of tissue they should become.

Using this as a start point, the MASC project is preparing all the techniques that would allow this process to be replicated within the lab. “We will be able to precisely locate growth factor releasing drug delivery systems with an accuracy equivalent to the width of a single cell,” Professor Shakesheff explains. “Then, by controlling the way the growth factor is released from the drug delivery systems, we can re-create gradients of growth factors in three-dimensional space.” In order to do this, the MASC team will utilize holographic optical tweezers to move single cells accurately within this three-dimensional space and “draw” tissue like structures. “We are trying to do this with a level of precision that occurs within the embryo.”

With the materials and tools developed as part of the MASC project, Professor Shakesheff and his team believe that there are three broad classes of patient who would benefit from the research.

• P eople who have suffered tissue damage as the result of a physical injury. This could be in a form of damage to tissue, muscle, bone, cartilage, part of the skeletal system, or it could be an internal structure or even traumatic injury to the head or damage to the nerves • P eople who have suffered tissue damage, or tissue loss, due to disease. For example, cirrhosis of liver, or liver cancer, where a lot of the liver has had to be removed. Also, heart attacks or cancers that affect most parts of the body’s tissues structures. If those tissues damaged by disease can be recreated, then medical treatment can be provided to restore tissue function • P eople with congenital defects, where tissue forms incorrectly in the first place

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Professor Shakesheff explains that the particular focus at the moment for the project is the growth of bone tissue.

“Bone is an interesting tissue; it has structural function, and within the bone marrow is a major site of haemotopoesis, and the formation of various blood cells,” he says.

Professor Shakesheff hopes that the tools and materials that have been created throughout the MASC project will be very generic, and so will enable other researchers to build upon the team’s results and produce different tissue types.

“Once you can precisely define the conditions within your scaffold, other people can take that technology further,” he says. “If you look at every tissue of the body, it is the same basic rules that are used to form that tissue, the same concept that you need to control in a threedimensional environment at the level of a single cell.”

The project is currently in the process of developing the fundamental tools that would allow the construction of the tissue structure. Working in collaboration with the University of Glasgow, the MASC team will be using a machine that will enable the “drawing” of cells in 3D. “Once the machine is up and running,” Professor Shakesheff tells us, “it could be used by many different groups of researchers, so we want to demonstrate that it works very robustly.”

The team are also working on the production of the growth factor gradients.

By using growth factors synthesized in the lab, the team will then form them into a pharmaceutical device known as a microparticle. The growth factor is encapsulated within a polymer shell which is designed to release the growth factor over an extended period of time. “We are using that as a way of creating growth factor gradients,” Professor Shakesheff says. “It is a very generic tool, and once we’ve got it working it could be applied to virtually any growth factor.”

One of the key points of the MASC project is its multi-disciplinary nature. It is not only dealing with synthetic materials science, but it also encapsulates nanotechnology, stem cell science, and developmental biology. As Professor Shakesheff explains, “the attraction of this project is that there is an opportunity to weave all of these different area together towards one common goal.”

At a glance Full Project Title Materials that Impose Architecture within Stem Cell Populations Project Objectives The project will create new regenerative medicine product opportunities by incorporating ideas from developmental biology into new scaffolds and cell therapies.

Project Funding ?2.3 million Contact Details Project Coordinator, Professor Kevin Shakesheff Head of School of Pharmacy Centre for Biomolecular Sciences University of Nottingham University Park Nottingham NG7 2RD T: +44 11595 101 E: kevin.shakesheff@nottingham.ac.uk

Professor Shakesheff

Project Coordinator

Professor Shakesheff’s inventions and scientific breakthroughs have resulted in 180 peer-reviewed papers and 4000 citations. He established 2 companies and has won numerous international rewards. A leading figure in shaping UK interdisciplinary research, he established a 320 researcher Centre for Biomolecular Sciences. In 2009, he became the Head of the School of Pharmacy and is a member of the Medicines and Healthcare Regulatory Authority Expert Advisory Group on Biologics and Vaccines. He is also a member of the Research Excellent Framework Panel 3A for 2014.

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