The New Cellular Industry

Each year, a few thousand otherwise healthy Americans slip into comas because of acute liver failure, the result of a virus, medication overdose or toxic mushrooms. Unless they receive an immediate liver transplant, most die.

But researchers at medical centers and biotechnology companies are working on artificial livers--innovative biomachines that use living cells in a mechanical device that would briefly do the work of the human liver. In early experiments, some deathly ill patients have been kept alive until surgeons found a suitable transplant. Some awakened from their comas and recovered completely, while others died.

This is the frontier of tissue engineering, the science of combining laboratory-grown cells with man-made materials to replace or repair human body parts.

Products of this new hybrid of chemistry, biology and engineering are already on the market, among them skin grafts that help wounds and burns heal and cell therapy for badly damaged joint surfaces.

Many other applications are in development: small arteries to return circulation to a dying limb or an ailing heart, an artificial pancreas to provide a natural flow of insulin to a diabetic, injectable agents that can restore bladder control to the incontinent, and laboratory-made tissues to restore damaged bone or cartilage.

But in recent years, the promise of tissue engineering has often outstripped reality.

One respected team of scientists, for example, grew a cartilage shield to close a gap in the chest wall of a Massachusetts boy. A picture of the boy, flying through the air on his mountain bike, was featured in a Business Week magazine article on “biotech bodies.” But the researchers say they are still uncertain how successful the cartilage graft is and have yet to publish their results in a scientific journal.

Many scientists in this burgeoning field would like to turn down the volume and reduce expectations.

“After all the hype,” said Susan Sullivan of Organogenesis in Canton, Mass., “it will be nice to settle back down into the research mode.” Sullivan and others point out that it can take years, even decades, to move from promising animal experiments to successful human products.

Instead of focusing on fully formed replacement limbs and organs, the tissue engineers are concentrating on more achievable goals, such as building relatively simple body parts.

“Investors won’t hand you funding forever,” said Dr. Gary D. Gentzkow, medical director of Advanced Tissue Sciences in La Jolla. “The initial strategy is to go after those things that have the shortest timeline and the highest probability of success.”

Labs Grow Cells by the Millions

At the core of tissue engineering is the ability to take a few cells and grow them by the millions in the laboratory.

“You start with something little, you grow lots and lots of cells and then reconfigure them,” explained Dr. Joseph P. Vacanti, a professor of surgery at Harvard Medical School and Massachusetts General Hospital.

The aim is to produce tissues that are as durable as the parts they replace. And because they are made of living cells, they should be able to repair themselves and even grow after being implanted.

Perhaps the most eagerly awaited of these inventions is the artificial liver--not a fully developed, implantable organ, but a machine that can keep a patient alive through a crisis or until a transplant becomes available.

That’s especially important because there are not enough donor organs. Almost 12,000 patients are waiting for liver transplants--but only about a third will get the transplant surgery each year, according to data compiled by the United Network for Organ Sharing.

Now several companies are racing to develop artificial livers that can be hooked up for several days to clear a patient’s blood of otherwise lethal impurities.

When kidneys fail, patients can be kept alive with dialysis machines, but there has been no comparable means to do the work of the human liver. The liver performs a number of complicated but vital functions that can’t be duplicated by a strictly mechanical device.

The tissue-engineering solution is to grow millions of liver cells--from humans or pigs--and implant them alongside porous fibers or tubes in a machine that is hooked up to a patient’s circulatory system. The arrangement allows cells to do many of a healthy liver’s tasks, such as processing toxins produced in the breakdown of red blood cells. The machine also protects the cells from attack by the patient’s immune system, which would otherwise destroy them as foreign tissue.

Firms Test Devices for Liver Patients

At VitaGen in La Jolla, scientists are awaiting Food and Drug Administration approval to start a new round of trials for their “extracorporeal liver assist device.”

The device, built into a kidney dialysis machine, is initially intended for patients whose livers suddenly shut down, a condition most often brought on by an overdose of acetaminophen (found in painkillers such as Tylenol), a severe viral infection or eating poisonous mushrooms.

Unlike most of the experimental livers, the VitaGen device uses human cells--liver tumor cells that are easily grown in the laboratory.

Among the early patients was a 12-year-old girl who was treated after falling into a deep coma. Her liver function continued to improve through 58 hours of treatment, but she had to be separated from the machine because of problems in controlling her bleeding. Days later, she emerged from the coma.

“She is alive and well today, and this was done six years ago,” said VitaGen Vice President Terry Ryusaki.

The case does not prove that the device in fact saves lives, because there is no way of knowing whether the patient would have recovered without it.

VitaGen is now working with the FDA to win approval for tests of an improved version of the device. If the tests prove successful, VitaGen envisions expanding trials to include patients suffering from chronic liver disease and cancer, a worldwide market worth more than $1 billion.

Another artificial liver, developed by Circe Biomedical in Lexington, Mass., and a team led by Dr. Achilles Demetriou, chairman of the surgery department at Cedars-Sinai Medical Center in Los Angeles, is entering final testing in patients with acute liver failure.

This device uses pig liver cells to perform the functions of the patient’s failing liver. Of the first 22 patients tested on the machine, 20 have survived, including five who recovered without needing a transplant, Demetriou said in a recent interview. “If we could get our patients earlier, I think we could get even better results,” he added.

The company is gearing up to test what Demetriou calls a “bio-artificial liver” on as many as 150 patients over the next 15 months at hospitals in the U.S. and Europe.

Other companies working on devices using pig liver cells include Algenix in Minneapolis and Organogenesis.

Seeking to Create Skin, Cartilage and Arteries

Several biotech companies have developed products for healing wounds--artificial skin for severe burns, leg ulcers and bedsores.

Organogenesis grows cells from the discarded foreskins of circumcised newborns to create patches of living tissue, 3 inches in diameter, for treating venous leg ulcers, common in people with poor circulation. The product, called Apligraf and marketed by Novartis Pharmaceuticals, is also being tested for diabetic ulcers, bedsores and burns.

Advanced Tissue Sciences has a nonliving skin product called TransCyte for use as a temporary cover on severe burns. It’s also seeking approval for a living skin substitute called Dermagraft to aid foot ulcers in diabetics. Dermagraft, which is already marketed in Britain and Canada, also uses foreskin cells, which are seeded into a fabric of suture material that eventually dissolves.

LifeCell of The Woodlands, Texas, uses a slightly different approach for its skin product, AlloDerm, taking donated human skin gathered from tissue banks and stripping it of cells. The patient’s own cells eventually move into the graft, creating living tissue.

Several of these companies are working on techniques to produce small arteries to facilitate coronary artery bypass procedures or replace damaged blood vessels in the legs.

Today, most coronary artery grafts use segments of the patient’s own leg veins, but that requires a separate surgical procedure that can be painful. And patients requiring a second or third round of heart surgery may not have enough remaining veins for the procedure.

What is needed is an off-the-shelf product that can be used in any of the 400,000 to 500,000 bypass surgeries performed annually, said Organogenesis’ Sullivan. But it is likely to take years of animal testing before any product is approved for human application.

Some biotech firms are experimenting with engineered cartilage, the substance that gives shape to the human ear and nose and lines the inside of the knee and other joints.

Genzyme Tissue Repair of Cambridge, Mass., takes a patient’s own cartilage cells and multiplies them in the laboratory for use in knee repair. The product, called Carticel, promotes the growth of normal cartilage rather than scar tissue. But the procedure is complicated, requiring a specially trained surgeon, and recovery is slow. Company literature tells patients that they “may be able to resume low-level activities such as swimming, walking or biking as early as six months after treatment.”

Advanced Tissue Sciences is now growing small cartilage disks for aiding the repair of joint surfaces. The product is being tested in large animals and could be ready for human trials late this year, said Gentzkow, the company’s medical director.

Real Progress and Great Expectations

Biotech executives and researchers worry about meeting expectations in their nascent field.

“Academically, we have to crawl before we walk,” said Dr. Charles A. Vacanti, director of tissue engineering at the University of Massachusetts Medical Center and president of the Tissue Engineering Society.

The Vacanti brothers, Charles and Joseph, have drawn considerable attention for their work with cartilage. Along with Robert Langer at the Massachusetts Institute of Technology and others, they’ve been able to sculpt porous plastics into a variety of shapes, then seed them with cartilage cells. A decade ago, they grew cartilage in the shape of the human ear and kept it alive under the skin of a laboratory animal.

The experiment gained national attention in 1994 “when the press grabbed hold of it,” Charles Vacanti said. The experiment was intended to show that cartilage could be grown into made-to-order parts that would retain their shape in the body, he said--not to produce a usable ear.

It would be a mistake, he said, to apply the technology to “something purely cosmetic” because with existing techniques, the match would not be good enough.

The Vacantis and their colleagues have also been hailed for treating a boy born with Poland’s syndrome, a rare condition that left him with a hole in his chest wall the size of a tennis ball. His heart could be seen beating beneath the skin.

The usual treatment is to cover the opening with a flap of the patient’s own muscle. But because the boy played baseball, the Vacantis and their team also fashioned a protective plate for the boy, made from a polymer mesh seeded with cartilage cells taken from the boy’s body and grown in a laboratory.

The surgery has been widely hailed as a triumph of tissue engineering, but Charles Vacanti describes the result as “less than perfect.” The muscle has given the boy’s chest normal contours and protects his heart. But whether the cartilage made a difference is uncertain. “I personally do not feel the tissue-engineered cartilage was a major component,” Vacanti said.

This summer, Vacanti’s team at the University of Massachusetts created a replacement digit for a factory worker who lost the end of his thumb in an industrial accident.

The researchers carved a new finger from a piece of coral and seeded the porous substance with the patient’s bone cells. But the new thumb is still a work in progress. To make it fully functional, the team will try to coat the end of the replacement bone with cartilage and connect it to muscle so it can be flexed.

The Vacantis are careful to qualify the accomplishments of their young field, even as they promote its development.

“It’s important to generate enthusiasm, but not out of proportion to where we are,” said Joseph Vacanti. “We’re still in the embryonic stages.”

(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)

Rebuilding a Body

Tissue engineering is a burgeoning science that combines biology, medicine and engineering to produce materials that can be used to replace or repair human body parts. It is being used to make grafts to treat burns and bedsores and to make new bone, cartilage and short lengths of blood vessels. In other cases, the living cells are placed in devices that function as artificial organs.

Building a Scaffold

A scaffold, which is needed to give shape to these tab-made tissues, can be built from a variety of materials-- a fabric woven out of dissolvable sutures, from a chunk of sterilized coral or from natural proteins and plastics. Some of the materials are typically designed to dissolve away, replaced by the cells in the implanted tissue. The scaffold must be biocompatible--that is, not likely to be attacked by a patient’s immune system.

Here’s how it’s typically done:

1. Cells are collected from an animal, a donor organ, an established human cell line, or the patient’s own body.

2. Cells are grown in a bioreactor, where a liquid flow of nutrients allows the cells to divide--making millions of new cells from the few first collected.

3. The scaffold is seeded with cells, often using natural glues to hold them in place..

4. The result is living tissue that can be packaged for delivery to surgeons.

5. The tissue engineered graft is implanted in the patient.

Source: After a schematic provided by Advanced Tissue Sciences. *

Times staff writer Paul Jacobs can be reached via e-mail at paul.jacobs@latimes.com.