Regenerative Medicine
extra cellular matrix
When a hobby-store owner in Cincinnati sliced off his fingertip in 2005 while showing a customer why the motor on his model plane was dangerous, he went to the emergency room without the missing tip. He couldn't find it anywhere. The doctor bandaged the wound and recommended a skin graft to cover the top of his right-middle stub for cosmetic purposes, since nothing could be done to rebuild the finger.
Months later, he had regrown it, tissue, nerves, skin, fingernail and all.
This particular hobbyist happened to have a brother in the tissue-regeneration business, who told him to forego the skin graft and instead apply a powdered extract taken from pig's bladder to the raw finger tip. The extract, called extracellular matrix, lays the framework that cells use to generate any given body part. It's like a cellular scaffolding, and all animals have it. It holds the signals that direct cells to divide, differentiate and build themselves into a specific form.
Extracellular matrix is a component of body tissue that functions outside of the body's cells (thus the "extracellular" designation). It's made up mostly of collagen, a type of protein. So extracellular matrix extracted from the bladder of a pig does not actually have any of the pig's cells in it.
In human fetuses, the substance works in concert with stem cells to grow and regrow everything from heart aortas to toes. Fetuses can regrow almost anything that gets damaged while in the womb. Scientists have long believed that when a fetus reaches full development, this extracellular matrix stops functioning. But with evidence that applying extracellular matrix from a pig can initiate certain types of regeneration in humans, they're wondering if they can trigger human extracellular matrix to start working again. After all, according to regeneration researcher Dr. Stephen Badylak of the University of Pittsburgh, children up to the age of two have been known to regrow fingertips with no outside help.
Pig-extracted extracellular matrix is already used by veterinarians to help horses repair torn ligaments. In people, it's used to treat ulcers, closing a hole in the tissue that lines the stomach. It employs an entirely different process than the typical mammalian healing mechanism. Let's take the case of a person who loses the tip of a finger. When the finger is severed, the cells die, and their contents seep into the surrounding tissue. This alerts the immune system to a problem. The immune system's response to cell death is inflammation and scar tissue. The formation of scar tissue prevents any future cellular development in the area. That's why scars last -- cells are prevented from doing a repair job on that skin.
But when extracellular matrix is applied to a wound, it doesn't trigger an immune response. Instead, when it begins to break down into surrounding tissue, it causes the cells in that tissue to start repairing the damage the way they would in a developing fetus (or a salamander that loses a limb) -- they divide and rebuild, creating new, normal tissue, not scar tissue.
Combined with developments in stem-cell research, this extracellular matrix may work miracles in the area of regeneration science. As of early 2007, testing of the effects of extracellular matrix is being carried out on a military base in Texas. Scientists are using the powdered pig extract on Iraq War veterans whose hands were damaged in the war. They're opening the wounds and applying the component to finger stubs in an attempt to regrow them. The researchers conducting the study say they don't expect to regrow the entire finger, but are hoping to regrow enough of a finger to allow for some utility. They don't believe it will regenerate bone, but nothing is for sure right now. That man in Cincinnati had only lost his finger tip, at the lower part of the nail; he hadn't lost the entire finger.
Help from pigs aside, many wonder if the extracellular matrix in humans is unable to function or is simply in a latent state, awaiting some sort of trigger. Do humans in fact have the same regenerative capacity as salamanders, which can regrow an entire limb, and researchers just haven't found a way to activate the mechanism? It's not just amphibians that can regrow body parts: Deer regularly regrow lost antlers, composed of bone, tissue, cartilage and skin -- the same things that make up human limbs. Could there possibly be an internal switch that would reactivate the regeneration capacity that humans possess in the womb? Regenerative medicine is actively pursuing answers to these questions. And in the meantime, if applying powdered pig extract to a snipped finger can in fact facilitate regrowth, the possibilities for medicine are startling. Spinal injuries, amputated limbs and damaged organs could all be coaxed back into a complete, healthy state if science finds the right combination of treatments.
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Andrews spoke to Dr. Steven Badylak of the University of Pittsburgh's McGowan Institute of Regenerative Medicine and asked if that powder was the reason behind Spievack's new finger tip.
"Yes, it is," Badylak explained. "We took this and turned it into a powdered form." That powder is a substance made from pig bladders called extracellular matrix. It is a mix of protein and connective tissue surgeons often use to repair tendons and it holds some of the secrets behind the emerging new science of regenerative medicine.
"It tells the body, start that process of tissue regrowth," said Badylak. Badlayk is one of the many scientists who now believe every tissue in the body has cells which are capable of regeneration. All scientists have to do is find enough of those cells and "direct" them to grow.
"Somehow the matrix summons the cells and tell them what to do," Badylak explained. "It helps instruct them in terms of where they need to go, how they need to differentiate - should I become a blood vessel, a nerve, a muscle cell or whatever." If this helped Spievack's finger regrow, Badylak says, at least in theory, you should be able to grow a whole limb.
Advances That Go Beyond Theory
In his lab at Wake Forest University, a lab he calls a medical factory, Dr. Anthony Atala is growing body parts. Atala and his team have built, from the cell level up, 18 different types of tissue so far, including muscle tissue, whole organs and the pulsing heart valve of a sheep. "And is it growing?" Andrews asked. Absolutely," Atala said, showing him, "All this white material is new tissue."
"When people ask me 'what do you do,' we grow tissues and organs," he said. "We are making body parts that we can implant right back into patients."
Dr. Atala, one of the pioneers of regeneration, believes every type of tissue already has cells ready to regenerate if only researchers can prod them into action. Sometimes that prodding can look like science fiction. Emerging from an everyday ink jet printer is the heart of a mouse. Mouse heart cells go into the ink cartridge and are then sprayed down in a heart shaped pattern layer by layer. Dr. Atala believes it's a matter of time before someone grows a human heart. "The cells have all the genetic information necessary to make new tissue," Atala explained. "That's what they are programmed to do. So your heart cells are programmed to make more heart tissue, your bladder cells are programmed to make more bladder cells."
Atala's work with human bladder cells has pushed regenerative medicine to a transformational breakthrough.
In this clinical trial at Thomas Jefferson Hospital in Philadelphia, Dr. Patrick Shenot is performing a bladder transplant with an organ built with this patient's own cells. In a process developed by Dr. Atala, the patient's cells were grown in a lab, and then seeded on a biodegradable bladder-shaped scaffold. Eight weeks later, with the scaffold now infused with millions of regrown cells, it is transplanted into the patient. When the scaffold dissolves, Dr. Shenot says what's left will be a new, functioning organ. "The cells will differentiate into the two major cells in the bladder wall, the muscle cells and the lining cells," he explained. "It's very much the future, but it's today. We are doing this today."
Repairing The Wounded
Today, one of the biggest believers in regeneration is the United States military, which is especially interested in the matrix that regrew Lee Spievack's finger. The Army, working in conjunction with the University of Pittsburgh, is about to use that matrix on the amputated fingers of soldiers home from the war. Dr. Steven Wolf, at the Army Institute of Surgical Research, says the military has invested millions of dollars in regenerative research, hoping to re-grow limbs, lost muscle, even burned skin. "And it's hard to ignore this guys missing half his skin, this guy's missing his leg," Wolf said. "You start asking the question, is there somebody out there with the technology that can do this for us?"
"You mean regrow the tissue?" Andrews asked. "The answer," Wolf said, "is maybe." At the burn unit at the Brooke Army Medical center, the very idea of regeneration brings a glimmer of hope.
Army Staff Sgt. Robert Henline was the only survivor of an IED attack on his Humvee north of Baghdad. "It's a great idea," Henline said, talking with Andrews about the military's investment into the new technology. "If they can come up with something that's less painful and can heal it with natural growth, without all this scarring, it's definitely something to check into."
Regeneration Race Goes Global
Several different technologies for harnessing regeneration are now in clinical trials around the world. One machine, being tested in Germany, sprays a burn patient's own cells onto a burn, signaling the skin to re-grow. Badylak is about to implant matrix material - shaped like an esophagus - into patients with throat cancer. "We fully expect that this material will cause the body to re-form normal esophageal tissue," Badylak said. And in a clinical trial at the University of Pittsburgh Medical Center, patient Mary Beth Babo is getting her own adult stem cells injected into her heart, in hopes of growing new arteries. Her surgeon is Dr. Joon Lee. "It's what we consider the Holy Grail of our field for coronary heart disease," Lee said.
The Holy Grail, because if stem cells can re-grow arteries, there's less need for surgery. "It's a big difference from open heart surgery to this," said Babo. "If people don't have to go through that, this would be the way to go ... if it works."
The Business Of Regeneration
Corporate America, meanwhile, already believes regeneration will work. Investment capital has been pouring in to commercialize and mass produce custom-made body parts. The Tengion Company has bought the license, built the factory, and is already making those bladders developed at Wake Forest that we told you about earlier. "We're actually building a very real business around a very real and compelling patient need," said Dr. Steven Nichtberger, Tengion's CEO. Tengion believes regeneration will soon revolutionize transplant medicine. Transplant patients, instead of waiting years for a donated organ, will ship cells off to a lab and wait a few weeks to have their own re-grown. "I look at the patients who are on the waitlist for transplant," said Nichtberger. "I look at the opportunity we have to build bladders, to build vessels, to build kidneys. In regenerative medicine, I think it is similar to the semi-conductor industry of the 1980s, you don't know where it's going to go, but you know it's big."
LINKS:
For more on regenerative medicine and organ transplants, check out:
The McGowan Institute for Regenerative Medicine.
The non-profit United Network for Organ Sharing.
The non-profit Organ Procurement and Transplantation Network.
The non-profit organ and tissue donation group, Gift Of Life Organ Donation.
Wake Forest University.
Tengion Company.
For more information on regeneration science and related topics, check out the following links:
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