Stem cell studies take time, but Arizona researchers say the wait is safer for patients – The Arizona Republic

The sheep are a little awkward, but on each step forward, their hooves come downstrong and assured.

John Szivek sees each movement asan encouraging sign because it meanshis research and experimental treatment areworking.

Szivek is a professor of orthopedic surgery and a UA researcher who is trying to figure out how toregrow lost bone inside a humanbody. He received a $2 million grant from the U.S. Department of Defense to research amethod to repair devastating bone injuries by using 3D-printed support structures in combination with stem cells.

He is one of many Arizona scientistsresearching stem cells with an eye towardclinical use and Food and Drug Administrationapproval for treatments. Stem cell treatments are part of an emerging field of regenerative medicine that focuses on repairing the body by regrowing lost or damaged tissue.

So far, stem cells are only approved by the FDA as treatments for certain blood and immune disorders.There are no other approved uses for thesecells outside of investigational clinical studies.

Research is ongoing, but scientists hope to someday use stem cells to treat avariety of conditions like arthritis, strokeor cerebral palsy.

The FDA is continuing to review new stem cell treatments, andresearch in the field is advancing rapidly, raising the possibility of more approvedtreatments.

Effectivecures or treatments aren't available for many of the conditions studiedby stem cell researchers, such as catastrophic bone injuries.

While bones have regenerative properties that usually allowthem to self-mend after a break, severe injuries and breaks can be nearly impossible to mend, especiallyif there is missing or dead bone. Even with surgery,such injuries can eventually require amputation.

In the military, such devastating bone injuries are more common as a result of explosions or combat injuries, and prevent thousands of soldiers from returning to active duty.

If Szivek's sheep study is successful, the treatment could be clinically tested in military personnel as thefirst step in human testing. The goal is to find a treatment that could help injured soldiers heal.In the study, researchers surgically removea piece of bone from sheeps' legs and place a 3D printed support structure with stem cells into the space.

In humans with bone cancer, bone is often surgically removed in a similar procedure, Szivek said, except dead bone is used to fill the space instead of a stem cell coated structure. These dead bones will eventually break, he said.

So far, Szivek said the sheep given his stem cell treatment are healing well.

"By sixmonths, the bone we grow looks almost identical to the type of bone that should be in the injury location," he said.

Butthere's still a lot that Szivek needs to do before the treatment would be approved by the FDA for use in humans. He needs to ensure that the treatment is standardized,but also needs to run controlled, scientifictests and collect extensive data to prove that the treatment works and is safe.

In response to questions from The Arizona Republic, an FDA spokesperson said the field ofregenerative cell therapies is promising, but that getting safety data is critical.

"These technologies, most of which are in early stages of development, offer the potential to improve human health, but they can also pose risks for patients," the spokesperson said in a written response.

Despite the potentialrisks, aRepublic investigation found that hundreds ofmedical professionals in the state advertisestem cells treatments for a variety of conditions that are not FDA approved.

The FDA issued a warning about unapproved treatments, calling some of themthem illegal and potentially dangerous. The FDA announced in 2017 that it would pursue greater enforcement of the rules and crack down on bad actors within the industry.

Arizona stem cell researchers saidthe methods usedfor unapproved stem cell treatments and approved stem cell treatment research are very different, which may cause unapproved treatments to be ineffective or even dangerous.

These researchers worry that damages from unapproved procedures could spur distrust in legitimate stem cell treatments.

To grow stem cells into bone, Szivek and his research team use 3D printers to create a porous-white tube with holes. The tube acts as a scaffold forthe stem cells to grow on and helps the cellsdevelop the right structure to become bone.

Thescaffolding methodis also being used by stem cell researchers for other types of tissue engineering. The shape, size and textureof the 3D printed scaffold used dependson the type of tissue or cells scientists are trying to grow.

In the case of Szivek's research, the scaffolds are created based on detailed CTscans, whichprovide a 3D rendering of a sheep'shind leg bone.

Once they've created a structure to guide cell growth, Szivek's team members extractstem cells from a sheep's fat tissue, removingany unwanted material.

"It's like an English garden, where there are all kinds of different flowers mixed together," Szivek said. "That's what you extract initially because you get the stem cells, you get some fat cells, you getsome immune cells in there, you get all of these cells."

Taking out unwanted cellsis a process that can take about a week. After that, researchers add ingredients that signalthe cells to changeinto the right material.Tn this case, that's bone.

For researcher David Lott, it'sthroat tissue.

Lott is the associate director at Mayo Clinic's Center for Regenerative Medicine inArizona and he's trying to use stem cells to replace missing vocal cords and up to half the voice box.

Because stem cells have the ability to turn into any type of cell, Lottneeds to use the right signals to guide the harvested stem cells to turn into the cell he needs.Those signals are sometimes referred to as growth factors.

Growth factors are proteinssecreted by cells tostimulate cellgrowth, specialization, survival, inflammationor tissue repair. Growth factors can becell specific; if researchers want to create bone, they usegrowth factors that are secretedby bone cells.

"Instead of asking them to passively turn into some sort of cell, you're actually actively making them turn into a different cell," Lott said. "So you have more control over that situation and the outcome is a lot more predictable."

Because it's more controlled, such treatments are less risky, more likely to work, and more likely to be approved by the government for medical use, he said.

Lott's team is researching thethroat treatment in the laboratory on dogs, but isworking with the FDA to get approval to test thetreatmentin humans.

"We're very close," Lott said, suggestingMayocould start human clinical trials soon.

Associate director at Mayo Clinic's Center for Regenerative Medicine David Lott points out different parts of the voice box that his team hopes to regrow and replace for patients who would otherwise lose it.Amanda Morris

If the treatment is approved for human use, the medicalbenefits could be enormous, according to Lott. The standard medical practice for people with throat cancer orthroat diseaseis to remove one vocal cord, half the voice box or the entire voice box.

"What happens when they have that trauma to that area is that they lose the their ability to speak, their ability to breathe or their ability to swallow," Lott said.

That'swhat AzraRahimic was told awaited her when she found out she had throat cancer.

In February 2018, she started feeling discomfort in her throat, and her voice started changing, growing scratchier.

She started losing her voiceand experiencing coughing fits. Eventually, it got harder for her to talk, and doctors told her she had throat cancer.

After unsuccessfulchemotherapy treatments, Rahimic said herformer doctor told her the only option was to remove her entire voice box. ButRahimic's daughter, Amila, refused to accept the idea that her mother would never be able to talk normally again.

Amila learned that Mayo Clinic was already testingthe scaffolding technique in some patients, althoughwithout the stem cells.

Mayohasapproval for a procedure in which doctors scan a patient'svoice box before any vocal cords are removed. This procedure is done to replace half the voice box.

"So once that scaffold is created, it's essentially a perfect fit for that specific patient," Lott said.

Instead of putting stem cells on the scaffold, Lott's team removes tissue, such as muscle, from elsewhere on the patient and puts it onto the scaffold to use as a replacement for the missing vocal cord or half of the voice box.

"The downside with that is that you are taking tissue from somewhere else where it should be," Lott said.

Rahimic said it took her weeks to recover, butover a month later, she was finally able to talk again.

"I heard my voice again andI thanked God for Dr. Lott," Rahimic said in May.

Rahimic's cancer came back in early September, so while the technique helped her initially avoid the removal of her voice box, she now needs a full laryngectomy.

Her original medical treatments could have been easier if Lott's team had used stem cells.

"Itdecreases the surgical time, decreases the complications that can come from the surgery andthe patient's pain," Lott said.

Mayo clinic researchers is working on regrowing lost or missing tissue on 3D printed scaffolds.Amanda Morris

Stem cells arecommonly researched for orthopedic treatments such as ligament or cartilage damage, but Lott said theyhave a variety of other uses too.

A sheep walks on a treadmill inside a University of Arizona lab, where researchers are trying to regrow missing bone.Courtesy of the University of Arizona

"Regenerative medicine applies to the entire body," he said.

At Mayo Clinic,research is ongoing to use stem cells as a treatment for conditions fromneurological disorders to cardiac disease.

"You can inject stem cells at the time of a heart attack, and you see a significant drop in complications from that heart attack," Lott said.

Szivek is also working on regrowing cartilage. It's more difficult, he said,because cartilage doesn't naturally have the same self-healing properties as bone.

"Cartilage is a pain," Szivek said. "Cartilage cells are typically fairly lazy. They don't divide. ... They don't repair cartilage tissue much, so pretty much the cells that you have in your cartilage tissue, they're sitting around having a nap."

Because of this, Szivek said cartilage created from stem cells can quickly break apartinside a bodyif it isn't built correctly. To grow the right type of cartilage, researchers must orient stem cells in specific directions to create the right structure. Cartilage in a person's ear is structured differentlythan cartilage in the knee, Szivek said, and wouldn't last if it grew inside a knee.

That's why he believes most unapproved stem cell injections to regrow cartilage don't work, even if some of them do initially show some cartilage growth aftertreatment.

"The cartilage material that forms is not necessarily sturdy," he said.

He said he wouldn't be surprised if a patientlost any cartilage that formed afteran unapproved treatment.That's why he believes careful, controlled research and clinical trials are necessary, and why it's also important to evaluate the long term effects of any treatment.

Though Szivek and Lott haven't yet started human trials for their research, they believethey are close. Other stem cell research is already in human clinical trials.

One trial currently underway at the Arizona Research Center aims to study stem cellsfortreating partial rotator cuff tears.

As of December, the research center hadenrolledabout 10patients in the study, but it was looking to get as many as possible, according to its chief medical director, Joseph Gimbel.

In this study, patients undergo an MRI to define the degree of their rotator cuff tear, then have stem cells extracted from their fat. Thestem cells are"washed" to remove unwanted material and tested to ensure they are safe before they are reinjected back into a participant'srotator cuff. After six months and again after a year,patientsundergo MRIs soresearchers can collect dataon how much their injury healed.

A 3D printer is used to create a scaffold on which lost or missing tissue can be regrown at Mayo Clinic.Amanda Morris/The Republic

What separates this clinical trial fromunapproved treatments is the level of safety involved, Gimbel said.

Before starting the study, he said areview board looked at every step of the process to ensure safety and control. Participants are also monitored for any side effects throughout the study.

At the end of the study, the Arizona Research Center will be able to offer exact data on the treatment's effectiveness.

That's because the study is controlled, meaning not everyone who enrolls will receive stem cells. Some participants will receive a placebo instead. This allows researchers to compare stem celltreatments to the placebo shotsand eliminate a potential bias called the placebo effect.

"Almost everybody out there offering stem cells is offering these unproven, potentially dangerous products," Gimbelsaid."They're charging a fortune."

Participants in a clinical study don't have to pay anything to enrolland will receive up to $450 for participating.

The research center's clinical operations manager, Rachel Gledhill, believesgetting more FDA-approved stem cell treatments on the market wouldpushunscrupulous actors out of business.

"When patients start saying, 'I don't want to get a shot from someone that hasn't done the research,hasn't done the testing, and I don't know where it came from,' you can't get $10,000 for it anymore," Gledhill said. "They're going to want an FDA approved product which will make people want to provide that."

A 3D printer at the Mayo Clinic in Scottsdale produces scaffolds on which researchers can grow stem cells.Amanda Morris/The Republic

Proper research takes a lot of time and resources. The Arizona Research Center has been running its rotator cuff stem cell study forover a year.

People who are ailing now may not want to wait for approval and might be willing to pay for treatments that are not approved.Butgetting unapproved treatments disqualifies people from participating in scientificstem cell studies.

University of Arizona stem cell researcher David Harris, believes thatstem cell clinics marketing unproven treatmentscould hurt researchers who are doing things the correct way.

"If it appears that ... medical professionals aredoing this just to make money, it will spur a lot of distrust, not only in the doctors, but also in in this field," Harris said.

Harris acknowledged that the process to get FDA approval for stem cell treatments can be long, but said it's necessaryto ensure safety.

"There are legitimate ways to do this, where you don't have to sort of operate under the radar or try to do it before the FDA cracks down," he said. "It's very easy to ... do these kinds of treatments under legitimate oversight. You can't charge an arm and a leg when you do that, but you can still charge a reasonable amount to cover cost. That doesn't seem to be the goal here."

Independent coverage of bioscience in Arizona is supported by a grant from the Flinn Foundation.

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Stem cell studies take time, but Arizona researchers say the wait is safer for patients - The Arizona Republic