Organs, both artificial and natural, hold the key to predicting and understanding how novel drugs will react in the body. Sean Ottewell investigates
If you have hay fever, headaches or a cold, it's only a short way to the nearest chemist. The drugs, on the other hand, can take eight to 10 years to develop. Until now animal experiments have been an essential step, yet they continue to raise ethical issues.
"Our artificial organ systems are aimed at offering an alternative to animal experiments," says professor Heike Mertsching of the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB in Stuttgart. "Particularly as humans and animals have different metabolisms. 30 per cent of all side effects come to light in clinical trials."
The test system, which professor Mertsching has developed jointly with Johanna Schanz, should in future give pharmaceutical companies greater security and shorten the path to new drugs. Both researchers received the Human-centred Technology prize for their work.
"The special feature, in our liver model for example, is a functioning system of blood vessels," says Schanz. "This creates a natural environment for cells." Traditional models do not have this, and the cells become inactive. "We don't build artificial blood vessels for this, but use existing ones - from a piece of pig's intestine."
All of the pig cells are removed, but the blood vessels are preserved. Human cells are then seeded onto this structure - hepatocytes, which, as in the body, are responsible for transforming and breaking down drugs, and endothelial cells, which act as a barrier between blood and tissue cells. In order to simulate blood and circulation, the researchers put the model into a computer-controlled bioreactor using a flexible tube pump developed by the IGB. This enables the nutrient solution to be fed in and carried away in the same way as in veins and arteries in humans.
"The cells were active for up to three weeks," says Schanz. "This time was sufficient to analyse and evaluate the functions. A longer period of activity is possible, however."
The researchers established that the cells work in a similar way to those in the body. They detoxify, break down drugs and build up proteins. These are important pre-conditions for drug tests or transplants, as the effect of a substance can change when transformed or broken down - many drugs are only metabolised into their therapeutic active form in the liver, while others can develop poisonous substances (Fig. 1).
The researchers have demonstrated the basic possibilities for use of the tissue models - liver, skin, intestine and windpipe.
Cell cultivation
Regenerative medicine researchers at the University of Pittsburgh in the USA have received two grants worth more than US$5million from the National Institutes of Health (NIH) to explore new methods for cultivating replacement cells from existing tissues and organs.
One grant, worth US$2.9 million, will be used by Eric Lagasse, a professor of pathology in Pitt's School of Medicine and a researcher in Pitt and UPMC's jointly operated McGowan Institute for Regenerative Medicine, to develop a novel concept: using the body's many lymph nodes as sites for growing replacement cells for other tissues and organs, in essence using them as bioreactors to grow cells within the living body.
Ipsita Banerjee, a professor of chemical and petroleum engineering in Pitt's Swanson School of Engineering and a McGowan faculty member, received his US$2.2million grant to unravel how embryonic stem cells develop into mature cells and possible techniques for influencing their growth to suit specific organs.
Lagasse's work focuses on lymph nodes, which are important in responses to bacterial and viral infection and are found throughout the body. Even spread out, the total mass of the nodes makes them a feasible place to grow liver cells, for example, which must also be available in abundance and with ample blood flow to provide life-sustaining hepatic function, Lagasse said.
His team will explore growing liver and other tissues in such 'ectopic' sites, meaning outside of where it would normally reside. The same principle of using lymph nodes as a site for ectopic cell factories might work for replacing pancreas cells that make insulin for patients with diabetes or immune system T-cells for patients who have AIDS and other diseases of immunologic-impairment.
"Our regenerative medicine approach for healing damaged tissues and organs might not have moved forward without this new grant concept," Lagasse noted. "This funding supports assessment and rapid translation from the bench to the bedside of non-traditional treatments."
Banerjee will investigate the process through which embryonic stem cells become mature, organ-specific cells and how scientists can control that development. Using a bottom-up approach, Banerjee will cultivate stem cells into pancreatic cells, noting molecular-level information that could be integrated into dictating cell development, such as the influence of environmental factors and gene and protein networks.
"I want to take a completely different approach to addressing the complex process of cell development, which will potentially advance our understanding of regenerative medicine and stem cell bioengineering as a whole," Banerjee said.
Meanwhile, a grant from the NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB) will provide funding for University of Miami (UM) college of engineering researchers to develop a novel bioreactor system that will control mechano-electrochemical environment for tissue growth and also provide on-line monitoring for the properties of engineered tissues. The two-year, US$735,000 grant will fund the work of Weiyong Gu and Charles Huang, professors in the department of biomedical engineering, to develop the novel bioreactor system for engineering tissue in vitro for implantation in vivo.
"Congratulations to Dr Gu and Dr. Huang for being awarded such a prestigious grant on behalf of the College of Engineering," said Dean James M Tien. "Funding from the NIH/NIBIB serves the college and university, and also opens lines of inquiry and exploration about how technology can be applied to reengineering the human body, a key focus of the College's research thrusts."
Tissue engineering research aims to develop functional substitutes for diseased or damaged tissues. In order to succeed, the mechano-electrochemical environment in tissue culture needs to be optimised.
"The new bioreactor system will provide innovative technology for tissue engineering, thus facilitating the development of functional replacement tissues that can be used in repairing damaged tissue, such as cartilage and intervertebral discs," says Huang.
There are two stages to the proposed project. The first stage will be to design and develop the bioreactor system and the second will test the system. This technology will help scientists understand the mechanisms of tissue growth and tissue degeneration.
"The long-term objectives of the work are to elucidate the causes of intervertebral disc degeneration, to develop strategies for restoring tissue function or retarding further disc degeneration and to develop novel, less-invasive diagnostic tools for disc degeneration," says Gu.
