This was, Badylak would later admit, the kind of outside-the-box experiment that would probably never get past a university animal-care committee today. His third-year cardiovascular surgery resident called the operation “cruel” and “ridiculous” and refused to participate. Even Badylak’s habit of referring to the dog by name was contentious, since researchers typically conform to the colder convention of identifying laboratory animals by numbers. But when Badylak arrived for work the morning after Rocky’s surgery, he found the mutt wagging his tail and ready for breakfast.
Badylak kept expecting the dog to die, yet every day he would find Rocky healthier and more energetic than the last. Days turned to weeks and Rocky continued to thrive. “I didn’t want to go in surgically and look because I wanted to see how long the intestine would hold,” he says.
Hoping to make sense of his unexpected result, Badylak repeated the procedure on 14 other dogs. They, too, thrived. Six months later he finally operated on one of the dogs to understand why. That, he recalls, is when “things got really weird.” Badylak could
not find the transplanted intestine.
After checking and double-checking to make sure he had the right animal, he placed a piece of tissue culled from the transplant target area under a microscope. What he saw floored him. “I was looking at something that wasn’t supposed to happen,” Badylak says. “It went against everything I had been taught in medical school.” Under the glass he could still see traces of the sutures, but the intestinal tissue was gone. The aorta had grown back in its place. “Nobody would confuse an intestine and an aorta,” Badylak says. “The microscopic picture is entirely different. I tried to get everybody I could think of to look at it. I kept asking, ‘Am I seeing what I think I’m seeing?’ ” Intestine is composed of soft, smooth, thinly lined walls, with hairlike projections known as villi. Aorta is thick, with the meaty, striated layers of the tissue that characterizes muscle.
Badylak examined several other dogs in the weeks that followed and watched the intestinal tissue transform again and again. He began to suspect that something in the intestine was suppressing inflammation and simultaneously promoting regeneration. Thinking back, he recalled a bizarre finding on liver regeneration he had heard about in a veterinary school pathology lecture: If you eat poison and it destroys all the cells in your liver, the organ can still regenerate, but only if its structural scaffolding remains intact. Destroy the scaffolding and the body responds by producing massive scar tissue and no regeneration. Perhaps the scaffolding was the key.
The next step, then, was to strip away the layers of the intestine, including its mucosal and muscle strata, until he was finally left with a paper-thin sheet of connective tissue called the extracellular matrix—the magical ECM.
When he replaced the dog intestine with just this tissue, the transplant still worked. Badylak repeated the experiment, this time using ECM derived from cat intestine. He was sure the dog’s immune system would reject the cat gut, but once again the transplant was successful. At this point Badylak realized he would be working with small intestines for a long time, and he was going to need lots of them. So for his next experiment, he used intestine obtained from one of the many pig slaughterhouses dotting the Indiana countryside surrounding Purdue. There would be no shortage of material if it worked. He tried it and, sure enough, his test dog was up and waiting for breakfast the day after it received the first of Badylak’s pig intestine transplants. (Porcine entrails—not only intestines but bladders, which were found effective as well—have been a staple in the doctor’s laboratory ever since.)
As for Rocky? He lived another eight years.
Badylak had solved the mysterious “how” of Rocky’s miraculous recovery. Now he faced a much larger enigma as he contemplated the “why.” He relentlessly pursued answers in the lab; at the same time, he eagerly looked to expand the medical applications for ECM. If it healed, why not start using it right away? People took aspirin for 30 years before anyone understood how it worked, he reasoned.
So Badylak moved the focus of his experiments from the large aortic artery to large veins. The pig intestine worked there. Then he found the material worked on small arteries, too. Finally, in 1989, he conducted a more radical experiment, removing a chunk of a dog’s Achilles tendon and replacing it with pig ECM. The normal response of any mammal’s body to significant damage is to create scar tissue, a hasty but crude way of replacing what has been lost. Scar tissue has a clear evolutionary advantage: The body is quickly sealed off from bacterial infection, and the injured creature has a better chance of surviving. A cut to the Achilles tendon normally produces a stiff lump of scar tissue that causes the animal to limp. Badylak’s dogs grew their entire tendons back. They developed no scars, and hence no limps.
In 1992 Purdue’s patent lawyer mentioned Badylak’s work to another client, an orthopedic device manufacturer called DePuy, based in nearby Warsaw. Like everyone else, executives at DePuy were initially skeptical. “It sounded like magic,” recalls Richard Tarr, who was then DePuy’s vice president of research and development. “But I have learned in research that you never stop listening. You can always say no.”
Badylak delivered a detailed presentation on ECM to a team at DePuy and explained that he had created a three-centimeter gap in the hind-leg Achilles tendons of three dogs. Then he left and returned with three 50-pound hunting dogs that bounded in and jumped up on their hind legs to greet the visitors. Tarr ran his fingers over one mutt’s hard, newly regrown Achilles tendon. Three months later DePuy licensed Badylak’s ECM-derived “biologic scaffolds” for all orthopedic applications. Suddenly Badylak had an industry sponsor to push for FDA approval, as well as $250,000 a year to continue his research.
It was around this time that Badylak first met Alan Spievack, a Boston-based surgeon who approached Badylak after he delivered a lecture on ECM at an orthopedic conference in Atlanta. As an undergrad at Kenyon College in Ohio in the 1950s, Spievack had performed amputations on salamanders and studied the way the creatures regenerated their limbs. He went on to a long, successful career as a surgeon. But Badylak’s talk rekindled Spievack’s fascination with tissue regeneration, and he persuaded the researcher to join him for a cup of coffee. Spievack visited Badylak’s lab and soon after joined the growing number of researchers who had begun pursuing their own research on ECM.
Despite this flurry of independent investigations, the true mechanism of ECM’s healing power was still unknown when Badylak sat down for a series of meetings in 1996 with representatives from DePuy and the FDA to discuss plans to begin initial testing of biologic scaffolds in humans. He worried that this missing piece of the puzzle would be a deal breaker. There was not much information to go on. ECM was known to be the glue that holds tissue together, a cellular-level skeleton upon which nerve, bone, and muscle can plant themselves and get to work. It is composed of some of the body’s most enormous protein molecules—laminin, collagen, and fibronectin—woven together in an intricate, seemingly impregnable web to form a scaffold. Few scientists had ever suggested ECM was anything more than a dumb structural element.
To Badylak’s surprise, the FDA investigators did not seem especially concerned about the mechanics of the scaffolds. DePuy had developed a patch composed of 10 layers of the material laminated together, which it intended to market for use in rotator cuff repair. And the company had come up with a strategy to win quick FDA approval. DePuy combed the industry for already approved therapies with similar properties —and found a soft-tissue reinforcement patch already used in hernia repairs made from bovine heart tissue. Then company scientists sought approval through a truncated process called a 510k, arguing that Badylak’s pig scaffolds shared many of the earlier therapy’s characteristics. Never mind that the bovine product had no regenerative properties; if DePuy could win approval for pig bladder as a safe soft-tissue hernia repair method, doctors could legally use it off-label in other ways.