A single-minded focus on bringing scientific advances to patients has driven Anthony Atala's pioneering work in tissue engineering.
Turning tissue-engineering research into biotech products is no easy task. But Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, is intent on finding a way. In a recent landmark paper, his group reported the first human trial of tissue-engineered bladders1. Transplantation of the artificial organs in seven young spina-bifida patients proved just as safe as the gold-standard treatment—surgical reconstruction using intestinal tissue—and avoided its debilitating complications.
“The work has tremendous potential clinical benefits,” says David Joseph, chief of pediatric urology at the University of Alabama School of Medicine in Birmingham. Alan Russell, director of Pittsburgh's McGowan Institute for Regenerative Medicine, describes it as “the first example of a large, complex, 'thin' organ being regenerated in humans.” In the wake of Atala's work on hollow organs, solid organs represent the next major challenge for tissue engineering.
Trained as a pediatric urological surgeon, Atala became interested in the potential of tissue engineering to improve surgical outcomes and address shortages of donor organs during a 1990–1992 fellowship under Alan Retik at Children's Hospital Boston and Harvard Medical School. He remained there as a faculty member, dividing his time between surgery and research, until January 2004, when he took up his new post at Wake Forest University in Winston-Salem, North Carolina. The bladder is just one of many organs he has sought to regenerate; others include skin, urethras, blood vessels, cartilage, cardiac and skeletal muscle, vaginas, uteri, bone, kidneys and tracheas.
In tissue engineering, everything goes back to scar formation. Anthony Atala , Director of the Wake Forest Institute for Regenerative Medicine
“In tissue engineering,” Atala says, “everything goes back to scar formation.” Scarring, also known as fibrosis, underlies how tissues fail in disease—and how they are regenerated. In normal wound-healing, the body recruits collagen, fibroblast cells, bone marrow cells and cells from the wound's periphery, a recipe that is not sufficient to prevent a scar. Atala wondered what other ingredients would be needed to grow a tissue from scratch. Simply adding certain scaffold materials to a wound, he found, lessens the scar. And including tissue-specific progenitor cells reduces it even more.
Whatever the tissue he wants to generate, Atala searches for felicitous combinations of scaffolds and cells. The bladders, for example, are made by expanding urothelial and muscle progenitor cells from a patient biopsy and seeding the cells onto a bladder-shaped scaffold. After a few days in culture, the proto-bladder is overlaid with fibrin glue (for structural stability) and omental tissue (to provide a vascular bed) and promptly transplanted into the patient. Three months later the bladder is two-thirds grown; at six months it is similar to a normal bladder and the scaffold is fully degraded.
Since 1990, when he began the project, Atala has studied artificial bladders in four animal models, overcoming critical obstacles along the way. The first hurdle was simply getting the urothelial cells to survive and proliferate. For three years he tested countless culture conditions without success. Then one day the surgical bladder specimens arrived hours late, so he skipped the collagenase treatment used to dissociate the cells and simply scraped the cells from the specimens manually. Two days later, the cells were proliferating.
Another challenge was finding a good scaffold material. If the scaffold degrades too quickly, the bladder collapses; too slowly and the bladder becomes fibrotic. Atala's scaffolds, of collagen and polyglycolic acid, last for a few months until the bladders can survive without them.
But perhaps the most formidable problem was simply creating an organ as large and thick as a bladder, which requires extensive vascularization. In vitro–engineered tissues cannot generally be grown thicker than about 300 μm because the cells at the center lack nutrients and oxygen. Atala's solution was to enlist the body as a “terminal incubator”: although the scaffold is formed and seeded with cells on a benchtop, most organ growth takes place in the body, where vascularization occurs spontaneously. As Atala notes, however, this method of vascularization is limited to hollow organs and would not apply to solid organs like the heart and liver.
Atala's clinical trial is only a first step towards made-to-order bladders. Further progress will involve refining the fabrication method, studying more patients and examining more endpoints. Joseph cautions that because of the children's underlying disease, the bladders lack proper innervation and do not void, requiring long-term catheterization. But the organs may function normally in other situations, he says. “Tony's approach opens up new avenues for people who have lost all or part of their bladder from a tumor, for example.” Tengion, a biotech company in King of Prussia, Pennsylvania, intends to take Atala's work forward in phase 2 and 3 trials.
Meanwhile, Atala himself has turned his attention to engineering other organs with the help of his new institute at Wake Forest. In Boston he had grown weary of the turf wars that can slow the translation of tissue-engineering research to the clinic, an effort that depends on multi-disciplinary collaborations and broad institutional support. Thus, when he was approached in 2003 by Richard Dean, president of Wake Forest University Health Sciences, to head a regenerative medicine institute of his own, he jumped at the chance.
“The institute is an experiment,” Atala says. “Unlike some tissue-engineering centers, it's not virtual.” Faculty members hold primary appointments at the institute rather than in a department, creating a strong culture of teamwork. “The structure of the institute does away with politics, with dual loyalties of the faculty. In a traditional institute, one is often faced with conflicts—who sends out the grant, and so on. Here, no one is fighting over grants and publications.” As a result, he says, the institute's scientists can focus on what is most important: “bringing technologies to patients, effecting changes in people's lives.”
Atala, A. et al. Lancet 367, 1241–1246 (2006).
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Aschheim, K. Profile: Anthony Atala. Nat Biotechnol 24, 1311 (2006). https://doi.org/10.1038/nbt1106-1311