It was one of the weirdest things I had ever seen. A hairless mouse with what appeared to be a human ear on its back. It was ten years ago that I made the
Tomorrow’s World film that brought this dramatic new image to a startled world. I remember that the mouse, however, was rather more interested in a female mouse than us, the cameras or its new appendage. And it was certainly unaware that it was soon to become an icon for a whole new scientific discipline — tissue engineering.
I’m afraid that Tomorrow’s World was as guilty of hype as any. The promise was of organs to go and an end to transplant waiting lists within five years. Ten years on and waiting lists for transplant organs are, if anything, even longer. What happened? Actually, quite a lot.
Tissue engineering is coming of age but has evolved differently from how anyone imagined. Rather than simply creating new lumps of tissue for transplantation, scientists are now excited at the potential of regenerating tissue within the body. And proof of the scientific seriousness with which it’s now considered came last week, with the launch at Buckingham Palace of a new charity, the Healing Foundation, which has tissue engineering and regeneration at its core and which will be funding major research into both. Later this year, the foundation will appoint the first academic chair in tissue regeneration.
The “traditional” tissue engineering approach, as exemplified by our mouse, involves growing complex 3-D structures, like a jawbone, or a windpipe or an ear. The recipe goes a bit like this. First create a mould of the body part required. Fill the mould with one of the new medical “biomaterials”, artificially produced substances that can integrate with living tissue. These act as a biological scaffold, creating the 3-D shape. (Such materials are Tardis-like in that, to the naked eye, they look very ordinary yet, under a microscope, they are full of space: a sort of car park for cells, providing thousands of nooks within which they can grow and divide.) Then scatter this material with cells taken from the patient, for instance, cartilage cells for an ear. Set aside until cells have multiplied and the scaffold has biodegraded leaving a 3-D structure.
The concept is simple. It sounds wonderful. So why no engineered kidneys yet? “The early promise has not been fulfilled,” concedes Dr Charles Vacanti, the researcher who put the mouse on the ear to find out what would happen when an engineered ear was replaced in a living organism. But now at Brigham and Women’s Hospital in Boston, an outpost of Harvard Medical School, he is still as passionate about the potential of tissue engineering.
“The train is still on track,” he says adamantly. But it has distinctly changed direction, with “repair and regenerate” triumphing over “replace”.
When it came to using tissue engineering for organ replacement, there have been three main problems — and one big new idea that changed everything. Problem one: it takes a long time to grow something to order; and that may be time the patient doesn’t have. Problem two: no one has yet cracked the problem of how to create a blood supply within larger tissue scaffolds. Problem three: there hasn’t been enough money in it for commercial companies to drive the technology. A decade ago, a whole rash of tissue engineering companies appeared but almost all have fallen by the wayside save those providing engineered skin for burns, or cartilage for knee injuries. So the field that had so much potential to restore function to those devastated by accidents, burns or disease still depends on research funding. Hence the need for a charity such as the Healing Foundation.
Then there was the big idea. A decade ago, the potential of stem cells, the cells which can become any type of cell, was almost unknown. But they are important because the cells needed to heal and to repair tissue are derived from stem cells. If you tear a ligament, it doesn’t heal itself. It sends out messengers requesting help, which bring in SWAT teams of stem cells to provide whatever type of new cells are required. “We now know much more about the key players in tissue repair,” say Gus McGrouther, the chairman of plastic and reconstructive surgery research at Manchester University.
All this means that the scientists’ attention has been diverted to creating tissue “on site”, rather than making body parts separately. It has another appealing advantage. We all know that muscle gets stronger if you use it, flabby if you don’t; bone, too, gets stronger with use.
Engineering tissues within the body means that they get the benefit of this stress and are more effective as a result. “We’ve realised the potential of harnessing the body’s own cells to make tissues in vivo,” says Professor Mark Ferguson, of the UK Centre for Tissue Engineering, also at Manchester.
The scientists there believe that the way forward is to reproduce the way the body produces tissues the first time, inside the womb. They believe the big idea for the next decade will be actually encouraging tissue regeneration, encouraging the human body to do what amphibians and starfish do when they lose a limb by accident: grow another one.
“We share the same genes,” says McGrouther, “and we need to find out what it is that is stopping them working after injury.”
The most likely spoiler for human tissue regeneration is likely to be our immune system. In the evolutionary scheme of things, we seem to have traded regeneration for a defence system. But what of Dr Vacanti’s work today? Like many other tissue engineers, he still believes in the scaffold concept, despite its problems. He has already published animal work in which movement has been restored to rats with newly severed spinal cords, using a tissue engineering approach. In this groundbreaking research, a bridging piece of scaffold material, placed between the cut cord ends, and seeded with nerve cells and growth factors, ended paralysis. He now hopes to do the same for dogs injured in accidents.
There might not be off-the-shelf ears, but the Japanese are already using tissue engineering to make a new pulmonary artery (the major blood vessel connecting heart and lungs) for patients in whom it has become too narrow or diseased to function properly. German researchers have replaced a whole jaw bone. In Britain, regenerative dentistry has started at King’s College London, which is attempting to grow new teeth in the mouth, ending the need for implants.
There are even inkjet printers for human tissue (see panel). Tissue repair, tissue engineering, tissue regeneration. Suddenly it’s all coming together. And not a mouse with an ear in sight.
INKJET HUMANS?
A key tool of the future for growing replacement tissues may be the inkjet printer. This “printer” would spray very thin layers (1,000 of them in 1cm) of material one on top of each other until the 3-D structure of the body part was laid down — a bit like building a topographical map, layer by layer.
The “ink” contains cells suspended in a nutrient- rich formula, which is seeded directly into each layer as it is “printed”. This ensures that cells get to every part of the structure.
This work comes from Professor Brian Derby, the head of materials science at the University of Manchester.
Because the exact contents of the “ink” can be varied with each layer, it allows more than one cell type to be created within the structures, making possible complex tissues such as bone.
