Monday, March 3, 2008

Body building

Engineering an elegant solution to the challenge of organ transplantation

Jay Vacanti, MD

If a starfish loses an arm, it simply grows another. If a salamander’s tail is severed, a new one develops. Regrettably, humans lack such an astonishing capacity to regenerate tissue or organs that are lost or rendered useless because of disease, injury or birth abnormalities.

For the most part, our only alternatives are artificial devices, harvesting tissue from one area of the body and grafting it to another or a tissue or organ transplant.  Yet none of these options is ideal by any means. Artificial devices – a kidney dialysis machine, for example – can be lifesaving, but as any dialysis patient will attest, it is a far cry from having a normal, functioning kidney.

Autologous (self) grafts require a major operation to harvest the tissue, which poses the risk of major complications, and the volume of harvested tissue is often insufficient. As for organ transplants, there is a woeful shortage of donor organs and for those fortunate enough to receive one, a lifetime of immunosuppressive drugs and their significant side effects awaits.

An enormous need

Millions of Americans need replacement tissue and organs, so finding a better alternative is critically important. Burn victims need skin, children with malformed jaws need bone, adults with diseased hearts need valves and vessels – the list goes on and on.

The most elegant solution would be to find a way to create permanent, living tissue that functions normally, including, in the case of a child, growing along with the patient. Ideally, it would be crafted from the patient’s own cells so that rejection is not an issue.

Sound farfetched? To some, perhaps. But 20-plus years ago, pediatric surgeon-scientist Joseph P. "Jay" Vacanti, MD, embarked on a research path that led him to conclude that creating, or “engineering,” a broad range of tissues – or, perhaps, even whole organs – was not only possible, but likely achievable during his lifetime.

Indeed, during his remarkable career, Dr. Vacanti, director of the Tissue Engineering and Organ Fabrication Laboratory within the Massachusetts General Hospital Center for Regenerative Medicine and surgeon-in-chief at MassGeneral Hospital for Children, has seen his innovative ideas evolve from concept to clinical reality. There are, for example, already five types of tissues in human use, and many dozens more are in preclinical studies, some of which are very close to being evaluated in humans. The field of tissue engineering, which was virtually non-existent 20 years ago, has grown to encompass thousands of researchers around the world conducting investigations involving all types of tissue and organs. At last count, the professional society founded by Dr. Vacanti had more than 2,000 members from dozens of countries. At least four start-up companies have been formed based on tissue-engineering technology platforms developed at Mass General.

Interdisciplinary by definitionDr. Vacanti is the first to point out that the remarkable advances and future promise in tissue engineering would not be possible were it not for the collective efforts of many scientists from a wide range of disciplines. “By its very definition, tissue engineering is a multidisciplinary research endeavor,” he says, adding that Mass General's long history of collaboration has made it a natural setting for this type of research.

Over the years, Dr. Vacanti has teamed up with a group of top scientists in varied fields – including his longtime collaborator, chemical and biomedical engineer Robert Langer, PhD, of Massachusetts Institute of Technology (MIT) – to tackle the formidable challenges inherent in recapitulating what nature does effortlessly: making tissue and organs.

This team, the composition of which changes depending on the task at hand, includes an eclectic mix of physician-scientists, basic researchers, materials engineers, chemists and cell biologists who hail from institutions throughout the Boston area – Mass General, of course, but also MIT, Draper Laboratories and CIMIT (a Mass General-based research consortium comprising 11 institutions) and, more recently, the Harvard Stem Cell Institute.

A complex processAlthough the idea is bold and the process enormously complex, the basic formula for tissue engineering, which was pioneered by Dr. Vacanti, is rather straightforward.

First doctors harvest the appropriate type of tissue-specific cells from the patient, and then “seed” them onto a biodegradable, polymer scaffold or matrix that is shaped like the tissue or organ they want to create.

The shape of the scaffold and other environmental influences provide critical cues to the cells; cells in a petri dish will never organize into, say, a blood vessel.

While the cells go about their normal business of proliferating, organizing and producing the extracellular matrix – nature’s own scaffolding – the temporary scaffold is simultaneously degrading or being metabolized until all that is left is the new tissue, which can then be implanted into the patient.

Whereas early scaffolds developed by Dr. Vacanti and his colleagues were comparatively simple, new materials and microfabrication techniques have made it possible for them to develop scaffolds of increasing complexity. These are being used to engineer complex structures such as blood vessels (which has already been achieved and used successfully in humans by a scientist who trained in Dr. Vacanti’s lab), intestines and even, Dr. Vacanti has little doubt, entire organs.

Currently the cells used to engineer tissue are usually obtained via a biopsy. But for some types of cells – heart valve or spinal cord cells, for example – a biopsy is not feasible. It is hoped that cutting-edge research in stem cell biology, which is taking place down the hall from Dr. Vacanti’s lab, may someday address this challenge by providing an unlimited new source of cells with the capacity to differentiate into any type of tissue.

Vital organs a priority

Under Dr. Vacanti’s leadership, the Tissue Engineering and Organ Fabrication Laboratory, which includes up to 30 Mass General-based researchers, is investigating a broad range of tissues and organs, from peripheral nerves and intestine to bone and cartilage. Dr. Vacanti’s highest priority, however, is work that will lead to the creation of vital   organs – the liver, for example – without which patients cannot survive.

“There is no artificial liver and there are more than 17,000 people awaiting liver transplants, most of whom will not receive one in time. For these patients, tissue engineering is the court of last resort,” says Dr. Vacanti, who, as director of pediatric transplantation for MassGeneral Hospital for Children, keenly understands the human toll of the donor organ shortage. “A great strength of the research enterprise at Mass General is that we never lose sight of the patient,” he says.

On the near horizon: implantable devices

While simultaneously working on the long-term goal of creating a liver and other vital organs, Dr. Vacanti and his team are currently developing fully implantable devices that would greatly improve the quality of life for patients with end-stage liver disease and chronic obstructive pulmonary disease.

“Until we can develop an entire organ, these devices would buy precious time for patients who are eligible for a transplant,” says Dr. Vacanti. “And for those who are ineligible for a transplant, they could offer a vastly improved quality of life, if not a longer life.” He emphasizes that with adequate funding, both the lung and liver devices could be ready for use in humans within as little as two years.

“Tissue engineering is an exciting, dynamic area of research that will have continuing human applications,” says Dr. Vacanti. “While we still have a lot to accomplish, we have the concepts and tools in place to achieve our goals in the foreseeable future. The science does work. The tempo of our work is constrained only by the lack of resources.”

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