The concept behind tissue engineering is simple: grow the patient’s stem cells in the laboratory, add them to a scaffold material, and you have a laboratory-grown organ. But few patients have benefited from this technology so far. Could change be on the horizon?
Scientific studies are frequently hailed as bringing novel, breakthrough treatments to patients. But the stark reality is that a long road must be travelled to turn a discovery in the laboratory into a viable clinical option.
For patients with severe gastrointestinal problems, new solutions are sorely needed; current medical treatments are marred with problems.
And complications such as this affect many people. For instance, babies with short bowel syndrome have a small intestine that is too short, making it unable to absorb nutrients properly. This condition affects around 25 in 100,000 newborns per year in the United States and can leave them with lifelong complications.
Short bowel syndrome can also occur when part of the intestine has to be removed due to cancer or other diseases.
Also, when the anal sphincter becomes damaged during childbirth – as a result of either cancer surgery or old age – patients can experience fecal incontinence. As many as 26 percent of women are reported to experience fecal incontinence after vaginal birth.
To address these problems, a research team from the Wake Forest Institute for Regenerative Medicine in Winston Salem, NC, has been developing new therapies for both anal sphincter injuries and short bowel syndrome.
But what is the likelihood of these new therapies ever reaching the patients, many of whom are in desperate need of better treatment options?
Khalil N. Bitar, Ph.D., a professor of regenerative medicine, explains the team’s approach, saying, “Our goal is to use a patient’s own cells to engineer replacement tissue in the lab for devastating conditions that affect the digestive tract.”
The small intestine is a complicated tissue. It consists of muscle cells that are essential for the contraction and forward propulsion of the food, as it moves through the gut. These cells must be aligned in a precise way to allow contraction to happen. Nerves are essential to stimulate the muscle cells to contract.
Similarly, in the sphincter, both muscle and nerve cells need to work closely together for normal function. This co-operation between different cells is one of the biggest challenges in tissue engineering. Although cells naturally grow and work together in the body, different cells are mostly grown in isolation in the laboratory.
Dr. Bitar’s team has spent years developing a precise method that allows them to grow muscle cells that are precisely aligned in one direction, and connect with nerve cells when they are added to the cell culture a few days later.
In a recent paper in published in Tissue Engineering Part C: Methods, the researchers transferred sheets of both cell types to small hollow tubes, which would make up the structure of the small intestine.
The tubes were then implanted into the lower abdomen of rats for 4 weeks, to allow blood vessels to infiltrate the structure. After this acclimatization phase, the tubes were attached to the small intestine of the rats, where they stayed in place for 6 weeks.
Importantly, the researchers found that after this period, the cells of the lining of the gut, or epithelial cells – which are essential for nutrient uptake from food – had started to migrate into the tube.
They also found food in the tubes, indicating that digestion was taking place and that this food was actively being moved through the tubes.
“A major challenge in building replacement intestine tissue in the lab is that it is the combination of smooth muscle and nerve cells in gut tissue that moves digested food material through the gastrointestinal tract,” Dr. Bitar explains.
“Our results suggest that engineered human intestine could provide a viable treatment to lengthen the gut for patients with gastrointestinal disorders, or patients who lose parts of their intestines due to cancer.”
Khalil N. Bitar, Ph.D.
The team is now planning to test the tubes in a larger animal model.
Their latest study, which is published in Stem Cells Translational Medicine this week, demonstrates the feasibility of using an engineered anal sphincter in a large animal model to restore fecal continence, something they have been working on for more than 10 years.
Building on their previous work in a rat model, they used a similar approach of combining muscle and nerve cells to produce a ring-like structure, which they then transplanted into rabbits with fecal incontinence.
Their results showed that after 3 months, the engineered sphincters were functional, with both the muscle and the nerves present. Fecal continence was restored in rabbits receiving the transplant.
Longer follow-up studies are currently taking place. But Dr. Bitar and his team are, of course, not the only researchers working on tissue-engineered solutions in this field of research.
Tracy Grikscheit, M.D., an associate professor of surgery and research investigator at the Saban Research Institute at Children’s Hospital Los Angeles in California, uses a mixture of cells taken from the intestine and adds them to a tubular scaffold structure. Her approach differs from Dr. Bitar’s in that it includes epithelial cells.
In the mouse study, muscle and nerve cells did develop in the graft, although they were not aligned the same way as native tissue, as Dr. Bitar is trying to replicate with his approach.
James Dunn, M.D., a professor of surgery and bioengineering at the Stanford School of Medicine in California, and his team have developed a new method of rapidly expanding intestinal stem cells. The long-term aim is to produce cells that can be used to treat different intestinal problems.
Levilester Salcedo, M.D., and Massarat Zutshi, M.D., of the Department of Colorectal Surgery at the Cleveland Clinic in Ohio, and colleagues used bone marrow stem cell injections to show improvements in anal sphincter function after removing 25 percent of the sphincter in a rat model.
Progress is clearly being made in tissue engineering of the gastrointestinal tract. But how soon will patients see the benefit?
Dr. Dunn told Medical News Today that to him, the biggest barrier to getting tissue-engineered intestine to patients is “to get all of the cell types working together in a co-ordinated fashion, followed by scaling the tissue-engineered intestine to [a] clinically useful dimension.”
In fact, most areas of tissue engineering suffer from the problem of scaling. Even though therapies may work very well on the scale of small rodents, making much larger constructs – such as stretches of small intestine for humans – is much more challenging.
Dr. Bitar told MNT that their plan for the small intestine graft is to test whether their findings hold true in large animal studies, which are very costly. “The biggest hurdle is the funding for such projects. With appropriate funding, it is reasonable to estimate [a] few years to [be able to] test in humans,” he explained.
Funding for scientific research has recently made headlines in the U.S. With a proposed overall cut to the National Institutes of Health (NIH) budget from $31.8 billion to $26 billion in 2018, funding across many areas of science is uncertain.
What is clear, however, is that patients need pioneering scientists to continue to search for novel treatments. And research funding is going to be absolutely key to turning these ideas into reality.