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Limb Transplant Gel: Saving Hands, Feet and Faces

When a person loses an arm or a leg and prepares for a transplant, rejection is always a concern. Patients must take immunosuppressant drugs for the rest of their lives to fight rejection, but the drugs can wreak havoc on the rest of the body. Now scientists have developed a new way to deliver the drugs to protect against rejection, changing lives in the process.

Painting and drawing for Richard Mangino is truly a gift. Each stroke created -without his hands.

Mangino told Ivanhoe, "When you have no hands, even though I felt like I could do what everybody else could do, people look at you like, well, he's got no hands."

But the quadruple amputee didn't let that stop him. He still painting with a hook and four years ago Mangino became the first successful double hand transplant patient.

"There are over 7-billion people on the planet, and they're not giving out hands everywhere. I was going to get them," he said.

Mangino can now easily mow his lawn, play piano, and take a drive.

Like other transplant patients, Mangino must take immunosuppressant drugs for the rest of his life.  Associate Professor of Medicine at Brigham and Women's Hospital in Boston Jeff Karp, PhD, says drugs  can damage the liver and kidneys.

Now researchers have developed a new hydrogel technology that can deliver immune suppressant drugs locally to minimize toxic effects.

Karp told Ivanhoe, "And we engineered it in such a way that it would only release the drugs in the presence of inflammation."

Karp says the new gel could potentially be injected just twice a year, rather than patients having to take daily pills.

Mangino exclaimed, "That's huge to people because we all just want to be like everybody else."

In a study in rats, researchers found the drug infused gel to be three times as effective as injecting the drug alone. Karp believes human trials could be three to five years away. To see more of Mangino's art and poetry, log onto richardmanginoartist.com.

BACKGROUND: Hand transplants are very rare but life-altering procedures. Worldwide, only around 40 people have received the procedure to regain the function and feel of a real human hand. People may receive limb transplants for various reasons such as accidents, birth defects, disease, etc. Many patients are offered a prosthetic limb which is an artificial body part that can function as a normal human limb but it does not have the look, feel or fluidity of a human body part. Many patients would much rather have a transplanted limb that looks normal, and can perform all of its normal functions rather than having a prosthetic limb. Now, doctors have discovered ways to use real human limbs to give amputee patients functioning tissues. Richard Mangino, amputee patient who received a hand transplant told Ivanhoe "When you don't have hands and you have a physical disability, people don't see you, they see your disability."

(Source: http://transplants.ucla.edu/body.cfm?id=116)

IMMUNE SUPPRESSIVE DRUGS: Even with the excitement of having a limb transplant, patients would still have to take immune suppressive drugs for life. Also called anti-rejection drugs, these are drugs that suppress or reduce the strength of the body's immune system. Because the body recognizes a transplanted organ or limb as a foreign object, the immune system would attack it. Patients would need to take these drugs in order to reduce the chance of the body rejecting the limb or organ that is transplanted from someone else. With taking these drugs come many risks. Because the immune suppressive drugs weaken the immune system, they are making the body susceptible to infections. Not only do patients face infection, Jeff Karp, PhD, Professor of Medicine at Brigham and Women's Hospital in Boston told Ivanhoe, "Patients typically need to take these drugs on a daily basis and when they start to feel good, they may forget to take those drugs. If they do, they can immediately incur a rejection episode and end up back in the hospital."

(Source: http://www.healthline.com/health/immunosuppressant-drugs#Overview1)

NEW TECHNOLOGY: In order to make the process of taking immune suppressive drugs easier and lower the chances of complications, Karp and his team have developed a new technology that can deliver immune suppressant drugs in order to prevent rejection of transplants. This transplant gel would only need to be administered every three to four months. Karp said "This could really reduce the toxic risks that these drugs pose."

(Soure: Jeff Karp, PhD)

Jeff Karp, Ph.D., Associate Professor of Medicine at Brigham and Women's Hospital, introduces a new gel that could help prevent rejection of transplants.

Interview conducted by Ivanhoe Broadcast News in February 2015.

What is the problem with transplants?

Dr. Karp: When we think about transplants, we often think of solid organs like livers, kidneys, or lungs. Recently, there's been a surgical innovation that has allowed transplantation of composites of tissues (multiple tissues put together). This can involve hands, limbs and even faces. One of the great challenges is actually an ethical challenge. These patients are often eligible for prosthetics yet face transplantation and limb transplantation or hand transplantation are not life-saving procedures. The challenge lies in that these patients need to be on immune-suppressive drugs for life because they are getting a limb, a hand or a face transplanted from somebody else. Overtime these immune-suppressive agents can wreak havoc on their bodies. It can lead to toxic effects in their livers or kidneys. It can also make them susceptible to all kinds of infections.

Without them, can you run the risk of rejection?

Dr. Karp: Right. Without the immune-suppressants, the patients run the risk of rejection. Many patients would much rather have a transplanted limb that looks normal and can perform some of its normal functions rather than having a prosthetic.

What you've been able to come up with is a new way to perform transplants without wreaking havoc on the body?

Dr. Karp: We've developed a new technology that can deliver immune-suppressant drugs to prevent rejection of the transplants. We can inject just under the skin of the transplant and this can last for months and months.

Is this localized to that particular area?

Dr. Karp: These injections are localized to the transplant itself. We've shown in our studies that we can minimize the systemic exposure of those immune-suppressant drugs. They are actually acting locally on the transplanted tissue to prevent the rejection but at the same time we can minimize the potential toxic effects.

What are these toxic effects?

Dr. Karp: The toxic effects could include liver toxicity, kidney toxicity or even making the patients more susceptible to infection.

How does this work exactly? It's like a gel, right?

Dr. Karp: We developed an inflammation responsive hydrogel. Hydrogels are materials like Jell-O for example, a material that has a lot of water in it. What we did is create a hydrogel that can encapsulate drugs. We put inside of that gel an immune-suppressive drug. We engineered it in such a way that it would only release the drugs in the presence of inflammation.

Is this something they would potentially use for the rest of their life?

Dr. Karp: We were able to show in our preclinical studies that if we do a limb transplant, the limb is rejected within 11 days if we don't administer any drugs. If we inject just the drug on its own into the limb, then it can survive for 35 days. If we put that drug into our gel system and inject that into the limb, the limb can survive for between 100 and 150 days. So, we envision that the drugs would only need to be administered every three or four months and it's possible through the reengineering of this gel, it could be less frequent.

How big of a breakthrough would you say this is?

Dr. Karp: We think this could have a substantial impact on the lives of transplant patients. This could reduce complications of the immune-suppressive agents that they need to take on a daily basis. This could improve compliance and reduce the toxic risks that these drugs pose.

You mentioned 11 days for a hand transplant, what about a face transplant? What's the risk of rejection there?

Dr. Karp: When you take any organ or tissue from somebody else and then you transplant them, it will be rejected almost immediately, within days or weeks.

How many hand transplants have been performed?

Dr. Karp: There have literally only been several handfuls of these procedures that have been performed. What we're hoping is that this type of technology could be used for many patients. This could improve the lives of patients across the globe who are looking for transplants and don't want to incur the risks of these immune-suppressive drugs.

Is there anything else you would like to add?

Dr. Karp: This was a highly collaborative effort involving a group in Switzerland. Robert Riebens, who has a very specific limb transplant animal model, and Praveen Kumar Vemula, who is a previous post-doc in my lab and now is faculty in India. We all really came together to try to solve this problem. Our next steps involve moving these studies to large animals such as pigs. If we can demonstrate efficacy there, we think we could push this into the clinic in the near future.

What have been some of the results from the small animal studies?

Dr. Karp: In Robert Riebens lab in Switzerland, he took a hind limb from a black rat and transplanted it onto a white rat and was able to show that with our gels, we could show sustained release of the drug for between 100 and 150 days. All of the animals that had transplanted limbs, their limbs survived for 150 days.

Were they functioning?

Dr. Karp: Perfect functioning. We were also able to show in our preclinical animal studies that there was no toxicity to be found in these animals. No liver toxicity or kidney toxicity.

Right now, there is such a shortage for organs. How difficult is it for the hand, leg or even face?

Dr. Karp: There's always a shortage of organ donors. There are many more patients that require transplants than there are donors to provide for. That's a huge unmet need as well. What we're hoping with our work is that we can improve the compliance and reduce toxic effects of the immune-suppressive drugs. Patients typically will need to take these drugs on a daily basis. When they start to feel good, they may forget to take those drugs. If they do, they can immediately incur a rejection episode and end up back in the hospital.