Beyond a Prosthetic
Written by Celeste Altus
MMT 2010 Volume: 14 Issue: 4 (June)
Some Scientists Opine That We May Only Be
A Decade or Two Away From a Day When
We Can Regenerate Human Body Parts
Every year men and women serving the country suffer traumatic injuries in the line of duty, from accidents and infections that cause amputation of the fingers to bomb blasts that take whole limbs. Scientists have developed sophisticated prosthetics to help veterans cope with the losses, but for some researchers, that is just the beginning. They want people to be able to benefit from what animals such as the tadpole and salamander can do: regrow entire limbs.
U.S. military researchers working together with academic institutions and private companies have a major initiative under way to learn how people’s genetic codes can be triggered to regrow limbs lost in the line of duty. This science is particularly timely, given conditions in the world today. Soldiers serving in Iraq and Afghanistan are suffering blast trauma at a much higher rate than other generations, due to the large number of roadside and suicide bombings in the two theaters. More than 900 personnel have had amputations since the start of the conflicts in Afghanistan and Iraq, according to defense authorities.
So this new effort, formed in 2008 and called Armed Forces Institute of Regenerative Medicine (AFIRM), is a consortium made up of laboratories from 15 of the nation’s top universities and medical centers, including Rutgers University and the Cleveland Clinic. With $85 million in funding split into two groups, the clinicians have been given a fiveyear timeline to develop innovative medical therapies specifically designed to treat wounded servicemen and women.
The two teams are led by Rutgers and the Cleveland Clinic, as well as Wake Forest University in North Carolina and the University of Pittsburgh.
Funding for the project is from multiple government defense agencies: The U.S. Army Medical Research Material Command, in conjunction with the Office of Naval Research, the National Institutes of Health, the Air Force Office of the Surgeon General and the Department of Veterans Affairs.
The $85 million is only part of the money available. The consortium will receive an additional $180 million from academic institutions and state and federal agencies along with industry, for a total of $250 million going toward the research of regeneration. Scientists involved in the project say they want to do all they can to advance limb regeneration.
“We’re doing this work because of our veterans, who have served this country so well,” said biologist David Stocum, Ph.D., director of the Center for Regenerative Biology and Medicine at Indiana University in Bloomington. “We want to be able to help them through this basic research. I just wish we could accelerate it to the point that we had an absolute army of people working on these projects, so that we could come up with it a lot faster.”
The AFIRM team will develop several clinical therapies during its five year duration. Included in those is burn repair, wound healing without scarring, craniofacial reconstruction, and limb reconstruction, regeneration or transplantation. The scientists will also work to address new therapies to prevent compartment syndrome, a condition related to inflammation after surgery or injury that can lead to increased pressure, impaired blood flow, nerve damage and muscle death.
The institutions put together teams of the best scientists to try to address these challenges.
Among them is Cleveland Clinic orthopedic surgeon Dr. George Muschler, AFIRM’s co-director along with Joachim Kohn, Ph.D., of Rutgers University. “The charge, and the reason for this investment, was to particularly focus on therapies that can be brought on quickly,” said Muschler. “It is of course true that those that are in danger now need these therapies now. They don’t want to wait 20 years to find therapy that could have helped them.”
He said the purpose of combining exceptional teams of scientists to research these therapies was to expedite the research cycle and the delivery of therapies.
“Significant advances were possible if resources could be focused on these challenges,” he said. “The programs that have been offered as part of AFIRM all have the goal of bringing forward new therapies [and] are either in clinical trials or are in the process of starting of clinical trials within five years.”
THE SCIENCE OF REGENERATION
When you think about it, limb regeneration in humans is not such a crazy idea. Humans have the ability to regrow bone, tendon, tissue and nerves in the tips of digits, if they are cut off at the last joint. “So there is some natural regeneration ability there,” Stocum said.
But in anything beyond a fingertip, regrowth is stopped because of the massive scar tissue that grows and covers the area to prevent infection and protect the rest of the body. And there are excellent examples in nature: lizards can regrow lost tails, and the axolotl, a Mexican salamander, can reform an entire limb after a loss.
Researchers such as Stocum are finding that the basic difference lies in the cells present at the injury site. His team’s work, some of which was published recently in the journal BioMed Central Biology, shows that the site of amputation in a salamander does not close over with scar tissue. New cells, called a blastema, form at the area and remain to regrow skin, muscle, bone, blood vessels and all the other components necessary for an embryonic limb bud. It’s as though the blueprint for the limb is right there, and the organism starts over on the growth process.
“People are trying to find out from the salamanders exactly what this process is. A lot of research has been done so far, but we still don’t know fully how this mechanism works.”
ADVANCES IN PROSTHETICS
This is not to say the area of prosthetics has not advanced significantly in recent years.
Worcester Polytechnic Institute in Massachusetts has been involved in bioengineering research to help amputees for many years, said Grant McGimpsey, Ph.D., director of WPI’s Center for Neuroprosthetics and BioMEMS.
Two years ago, the school received Congressional support from then-Senator Edward Kennedy and reached out to other institutions such as the University of Utah, where they are doing work on implanted prosthetic devices.
WPI has been progressing past the typical strap-on prosthetic leg that has been the same since the Civil War, McGimpsey said.
“And we are moving to a new paradigm where the body is regenerating tissues, or we’re helping the body regenerate tissues that can support, for example, a titanium post that has been placed in a limb,” he said.
The center’s mission is to help develop advanced implantable prosthetics that are integrated with the nervous system. It received a $1 million allocation from the U.S. Army Amputee Program in 2007, and another $1.6 million for the center was included in the recent Department of Defense appropriations bill.
While these particular allocations are directed toward research and development on advanced prosthetics, researchers affiliated with the center are also working on new developments in regenerative biology that are aimed at techniques that may enable humans to regenerate tissue, including replacement digits and limbs, eliminating the need for prosthetic devices.
McGimpsey said he’s hopeful about the advances the center has made, and he is pleased to be leading the research. “Personally, as a scientist, I wanted to be able to do something that would help amputees regain the use of their lost limbs,” he said. “I knew at the same time that WPI was the place to do it because we have a very strong engineering tradition here.”
AFIRM is not the only project in the works in this field. In 2008, a scientific team received $6.25 million from the U.S. Department of Defense to study the axolotl for its ability to regenerate body parts, with the hope that the knowledge gained will help scientists one day induce the regeneration of a human limb.
Fingertips are the extent of regeneration in humans at this point, unlike the axolotl, which can regrow limbs, jaws, skin, organs and parts of its brain and spinal chord.
Tulane University cell and molecular biology professor Ken Muneoka, Ph.D., is working at comparing the genome of the axolotl and the genes of a mouse— which are similar to those of a human—to “deduce what is missing and what [genetic makeup] correlates with a non-regenerative response.”
In an April 2008 article in Scientific American, Muneoka and his colleagues detailed the initial healing process after losing a limb, saying the process is similar in both salamanders and humans. Fibroblasts at the scene of the wound produce an extra cellular matrix; for humans and other mammals, “fibroblasts produce an excessive amount of matrix” that forms scar tissue. But salamander fibroblasts stop “once the normal architecture has been restored.”
In the article, the authors detailed that the key for scientists is to determine how to prevent the human body from forming scar tissue, and instead induce a blastema. Hope for human limb regeneration was raised last year when a 69-year-old man grew back half an inch of his finger using an extra cellular matrix powder made from cells scraped from a pig’s bladder.
Muneoka and his fellow scientists said they are very optimistic about the future of human regeneration. “The surprising conclusion is that we may be only a decade or two away from a day when we can regenerate human body parts,” they wrote.
Muneoka said his team’s research is basic in nature and focuses on animal models to understand how regeneration is controlled and to develop ways to enhance regenerative responses in animals that lack this ability, such as mammals Muneoka, who has been working on limb regeneration since the 1970s, started his research on salamanders that regenerate well and then moved on to the mouse as a model that is closer to the human in genetic makeup.
His lab’s work attracted the DoD’s Defense Advanced Research Projects Agency (DARPA) when it formed RIR, its Restorative Injury Repair program. RIR’s vision is to fully restore the function of complex tissue such as muscle, nerves and skin after traumatic injury on the battlefield.
The RIR’s focus includes injuries both kinetic, such as penetrating wounds, and other destructive injuries, like chemical and thermal burns, musculoskeletal injuries and blast overpressure. RIR aims to replace the current concepts of “wound coverage” by fibrosis and scarring with true “wound healing” by regeneration of fully differentiated, functional tissue.
“Our studies have shed light on how regeneration is controlled, and when DARPA developed the RIR program with the goal of transforming the typical wound healing response to traumatic injury to a response that regenerated functional tissues, we were one of a handful of research programs positioned to take on the challenge,” Muneoka said.
“In truth, DARPA chose us and presented us with the privilege to get involved with this project,” Muneoka said. “Since our research is basic, we are hopeful that we will be able to translate our successes in the mouse model to impact the human condition.” ♦