Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.
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Diabetic kidney disease (DKD) is a serious complication of diabetes. Up to 40 percent of people with diabetes eventually develop kidney disease. With no long-term treatment available, many patients will progress to end stage kidney disease requiring either dialysis or a kidney transplant. Research is underway to keep people from progressing to kidney failure, and the need for more invasive treatments such as dialysis or transplantation.
LaTonya Hickson, M.D., a Mayo Clinic nephrologist, is part of a research team looking at using stem cells to help regenerate failing kidneys.
“We take adipose tissue from a patient, harvest and expand mesenchymal stromal cells (MSCs), and later inject the cells into the patient’s injured kidney,” says Dr. Hickson. “Our hope is that these cells will then turn on the regenerative process to help delay the progression of kidney failure in individuals with diabetic kidney disease.”
Adipose-derived MSCs are stem cells that are taken from a patient’s abdominal fat and given back to the same patient. In this case, the cells are injected into the patient’s diseased kidney. Dr. Hickson’s latest research, a phase I clinical trial funded by a grant from Regenerative Medicine Minnesota, will assess the safety, side effects, dosing and timing of the delivery of these cells in patients with diabetic kidney disease.
“This research could lay the foundation for the development of a therapy that may dramatically affect millions of patients across the country by altering the trajectory of diabetic kidney disease,” says Dr. Hickson.
While there’s a lot more research ahead, Dr. Hickson is excited about the possibilities. She discusses the research in the video below:
One of the challenges of integrating regenerative medicine into daily patient care is that it is so new, there is not a lot of available data to consider when determining best practices. A recent grant will help track information on how patient do after clinical trials.
Regenerative Evidence-Based Outcomes Registry The Regenerative Evidence-Based Outcomes Registry (REBO) is a digital platform used to track patient experience and patient outcomes for regenerative medicine procedures. It is one of three aims of the Gerstner Regenerative Medicine Initiative. In addition to a data collection repository, REBO is designed to be a digital learning platform that can show prospective patients outcome data in terms of effective treatments based on clinical conditions and other factors in order to help guide patient decision making and provide greater opportunities to make regenerative therapies available elsewhere in the Mayo Clinic practice.
“In order to contribute to high-quality real-world data and real-world evidence, we have created the REBO registry to track patients over time,” says Shane Shapiro, M.D., associate professor of orthopedic surgery and medical director of the Regenerative Medicine Therapeutic Suites in Florida who heads the Gerstner Regenerative Medicine Initiative. “Unlike traditional outcomes registries, we include additional elements that incorporate ethics and social information related to health outcomes of these innovative therapies.”
This means that researchers can apply real-world data in addition to rigorous clinical study data to expedite understanding of treatments and further the development of regenerative medicine products while also using this information to inform patients about regenerative options.
“Clinical research trials are tightly controlled and often start with small patient numbers which will exclude a larger representation of our patient population,” says Dr. Shapiro. “There are many additional sources of real world data including the electronic health record, insurance claims and even data that patients are willing to share with their providers from their phones and devices.”
Dr. Shapiro and his team intend to combine their real-world data with ongoing clinical studies to advance regenerative medicine therapeutics. The data can also be pooled with that of other practitioners and investigators in the field.
The registry is built on a digital platform that can be customized to the needs of the practitioner as well as the health care field as a whole. This includes the ability to analyze the effect of medical comorbidities as well as behavioral concerns and mental health. The registry also weaves several medical and humanities specialties while educating and informing patients.
One of the first studies to use the REBO registry will track patient outcomes of shoulder and hip procedures.
“Almost all regenerative medicine clinical research is being conducted with knees,” says Dr. Shapiro. “By tracking patient outcomes for other joints, we can learn more about these procedures without even conducting additional trials.”
Regenerative Therapies for Knee Osteoarthritis In addition to the REBO registry, Dr. Shapiro, through the Gerstner Regenerative Medicine Initiative, is spearheading a study to develop evidence-based best practices for dosing and frequency of regenerative therapies for knee osteoarthritis. The trial uses stromal vascular fraction (SVF) cells, or stem cells from a patient’s own fat, to treat pain from knee arthritis.
“There are many clinics out there irresponsibly marketing SVF cells directly to patients without approval from FDA,” says Dr. Shapiro. “This is an important trial because it is one of the first using SVF cells conducted in a legitimate scientific fashion to determine safety and efficacy, with all of the appropriate regulatory approvals.”
In all, the Gerstner Family Grant supports five initiatives across Mayo Clinic’s Arizona, Florida and Minnesota sites. Two of the five initiatives funded through the grant are designated to advance patient care through enterprise-wide regenerative medicine research and clinical trials at Mayo Clinic. Read more about the Gerstner family donation on the Mayo Clinic News Network.
Watch an interview with Dr. Shapiro’s on how the Mayo Clinic Center for Regenerative Medicine is collecting real-world data to help inform patients, courtesy of The Evidence Base:
Baby Zane Fouts’ boundless curiosity starts at his feet, which he grabs and plays with happily. The energetic boy who’s full of smiles is a trailblazer for regenerative surgery performed in a clinical trial at Mayo Clinic even before birth.
“He’s our miracle baby,” says his mother, Alyse Ahern-Mittelsted. “He’s a rock star.”
Ahern-Mittelsted was 20 weeks pregnant when an ultrasound showed Zane had severe congenital diaphragmatic hernia (CDH). This life-threatening condition blocks lungs from growing enough for babies to breathe on their own. Without intervention, 70% of infants born with severe CDH die. The bombshell news came less than a year after Ahern-Mittelsted unexpectedly lost a daughter at 31 weeks of gestation to a different condition — a failed placenta.
“We thought we were going to lose another baby. We were really scared.”
CDH is a hole in the muscle separating the chest and abdomen. That causes the spleen, stomach and bowels to push up into the chest cavity and stunt lung growth. The result is small, underdeveloped lungs, known as pulmonary hypoplasia. It’s a rare condition that affects 1 in 10,000 babies.
“It’s a delicate procedure. We insert a 3-to-4 millimeter telescope through the mother and into the fetus. We advance a balloon into the baby’s mouth and detach it from a catheter placed insidethe trachea, which is the airway of the fetus. The goal of this surgery is to regenerate and expand the lungs,” says Dr. Ruano. “I feel so passionately about this surgery that I have dedicated my life to moving it toward standard of care treatment.”
When the balloon inside the fetus’ trachea inflates, it fills the lungs with fluid, potentially causing the lungs to expand and grow. Because a fetus breathes through the placenta, the balloon does not choke the baby.
While the surgery shows promise, it also comes with risk of preterm labor and delivery. That meant the young couple from Cresco, Iowa, had a decision to make about the health of their unborn child.
“We were told that without the surgery, our baby would only have a 25% chance of ever coming home. With the surgery, the chances jumped to 75%,” says Ahern-Mittelsted. “We knew there was a chance this surgery might not work. But, if this was going to give our son the best chance of survival, I wasn’t going to second guess it.”
“After the doctor told us our options, I was looking for more information (to help make a decision.) I looked online, but this procedure is so new, there wasn’t a lot about it. I had to put my faith and trust in our surgeon,” says Trevor Fouts, Zane’s father.
Surgery to place the balloon inside Baby Zane’s trachea was performed at 27 weeks under local anesthesia and took only about 15 minutes.
“When they were going to place the balloon, they had to move the baby and place him in the right position. That was painful for me, but it went fast,” she adds.
The balloon was removed at 34 weeks of pregnancy, and Zane was born full-term at 39 weeks. How well a baby with Zane’s condition does at birth depends on development of the lungs. Some babies whose lungs successfully grow and develop may recover with few lingering medical issues. Others whose lungs do not respond as well may have mild to long-term handicaps.
Immediately after birth, a breathing tube was placed in Zane’s airway and he was connected to a ventilator. But, he was only on machine-assisted breathing for a couple of weeks.
The balloon surgery expanded his lung capacity by about 60%. After 52 days in the Neonatal Intensive Care Unit, he had improved enough to go home.
“Without this procedure he likely would not have been as healthy as he is now. He still has a raspy voice and has a tough time with coughs. Eventually, we expect him to live a normal life with normal activities. We think he’ll be able to participate in sports, although he may need an inhaler,” says Ahern-Mittelsted. “I believe this surgery pretty much saved his life.”
Dr. Ruano has performed a total of five fetal endoscopic trachea occlusion surgeries so far at Mayo Clinic. His research team is compiling the data to establish whether this surgery improves chances for survival and reduces recovery time. The long-term goal is to secure FDA approval of the balloon used in the procedure so this surgery can be offered in daily clinical care.
Osteoarthritis is the most common form of arthritis, affecting millions of people worldwide. It occurs when the protective cartilage that cushions the ends of your bones wears down over time. While the significant pain, limited activity, and decreased quality of life that affect patients with osteoarthritis can usually be managed, the damage to joints can’t be reversed.
“One regenerative medicine option for those suffering from
osteoarthritis is the use of platelet rich plasma, or PRP,” says Dr. Finnoff. “While
there is mounting evidence that PRP injections may reduce pain and improve
function in people with osteoarthritis, we think we can make it better;
therefore, we’re looking to developing a safer, more effective alternative PRP treatment
PRP is made using a patient’s own blood. After the blood is
drawn, it is spun in a centrifuge which separates the cells and blood into
different layers. The concentrated layer of platelets, which is used for PRP, contains
proteins that are involved in the healing process and may also decrease
inflammation; however, PRP also contains some proteins that might trigger
inflammation of the breakdown of tissue.
“Our study involves trying to remove the inflammatory
proteins and those that might be involved in breaking down tissues from the PRP
so it has a stronger anti-inflammatory and healing affect,” says Dr. Finnoff.
“This is done by attaching proteins to tiny beads that bind to the proteins
that we want to remove from the PRP.”
Once a patient’s PRP product is developed, researchers will
then inject the new “purified PRP” back into the injured area to see if it is
effective to relieve osteoarthritis symptoms.
“Right now we treat osteoarthritis symptomatically with
weight loss, diet, exercise, braces, nutritional supplements, medications,
injections, and joint replacement surgery,” says Dr. Finnoff. “If we can
harness the healing potential of our body more effectively, we may be able to
slow the progression of arthritis or even reverse its course, revolutionizing
the treatment of osteoarthritis.”
Dr. Finnoff discusses his research in the video below:
With growing public awareness and broader academic engagement, the prospect of pioneering a change in disease management has propelled the field of regenerative medicine. The ability to build, scale and apply biotherapeutic technologies and solutions that are not cost prohibitive will become increasingly important elements that drive progress in regenerative medicine.
In a recently published paper, Mayo Clinic consultants discuss the evolution of regenerative medicine and the potential for biotherapeutics to revolutionize the reach of regenerative medicine applications.
“As validated regenerative therapies are increasingly adopted into the practice, there is an opportunity to evolve the healthcare paradigm and alter the economics of chronic disease management,” says Andre Terzic, M.D., Ph.D., the Michael S. and Mary Sue Shannon Director, Mayo Clinic Center for Regenerative Medicine. “At Mayo Clinic, we are paving the way with new know-how, technology and infrastructure that will make regenerative medicine more broadly available.”
“Stem cell-based therapy was fueled by the discovery and practicality of mining adult stem cells out of bone marrow and adipose (fat) tissue,” says Atta Behfar, M.D., Ph.D., the director of the Van Cleve Cardiac Regenerative Medicine Program at Mayo Clinic. “Until recently, regeneration was largely associated with the use of stem cells to restore function to damaged tissue.”
With ongoing progress, the current cell-centered focus will be broadened to encompass next generation advances in the science of biotherapeutics, including antibodies, cytoengineering, gene encoded therapy and exosome technologies comprising the regenerative medicine platform of the future.
“The milestones achieved over the two decade journey of cardiac regeneration have brought us ever closer to the prospect of biotherapies as a way to achieve the full potential of disruptive therapies for disease management,” says Dr. Behfar.
Mayo is developing broader regenerative medicine portfolios to make this a reality. Advanced product manufacturing is enabling a patient-ready toolkit to help accelerate broad availability of regenerative medicine to patients.
Today, experts across Mayo Clinic have access to resources that empower any medical, surgical, laboratory medicine or radiology specialty to advance new discoveries toward regenerative treatments. By integrating process development and manufacturing with quality control, regulatory and clinical trial competence, these translational capabilities collectively position the Center for Regenerative Medicine as an enabler in revolutionizing patient care.
The infrastructure required to achieve rapid translation of discoveries into broadly available transformative therapies for patients is essential to developing the future of medicine. The buildout of the Regenerative Medicine Therapeutic Suites in Florida, the first Discovery Square building in Minnesota and the Arizona Forward project are bringing regenerative medicine to patients in new ways and allowing for powerful collaboration to exist between Mayo and the world.
The grand opening of the new Discovery and Innovation Building at Mayo Clinic’s Florida campus signals a new era of integrating regenerative medicine into daily practice. Regenerative medicine seeks to tap the body’s ability to replace, restore or regrow damaged or diseased cells, tissues and organs. A hub of research and technology, the new building could advance new regenerative treatment options for lung disorders, transplants, arthritis, and many other conditions.
“It will bring us closer to our goal of making Mayo Clinic in Florida the regenerative medicine destination center of the Southeast,” says Abba Zubair, M.D., Ph.D., who specializes in transfusion medicine and regenerative medicine on Mayo Clinic’s Florida campus. “The Discovery and Innovation Building provides space that will significantly expand our capacity to support clinical trials in Florida.”
On the first floor of the Discovery and Innovation Building, Mayo Clinic and United Therapeutics Corporation are collaborating to combine expertise on United Therapeutics’ new lung technology known as lung perfusion technology. Lung perfusion is a pioneering technology that may increase the number of lungs available for transplant. It is a process by which marginal donor lungs are restored through flushing and ventilation while monitored in isolation. This preserves lungs for transplantation that otherwise would have been discarded. The lungs will be made available to patients at Mayo Clinic and other transplant centers throughout the United States.
In addition to lung restoration, researchers will use stem cells from healthy volunteer donors in the setting of FDA approved clinical trials to treat lung rejection (transplant related bronchiolitis obliterans), stroke, chronic obstructive pulmonary disease, interstitial lung disease, vascular fistulas and many more trials in the pipeline.
“We’re at a pivotal point in the field of regenerative medicine,” says Dr. Zubair. “We’re now able to expand our knowledge across specialties and are starting to look at scaling up production in order to effectively reach more patients.”
The building will also feature a Current Good Manufacturing Practices (cGMP) laboratory, which is important to assure proper design, monitoring, and control of manufacturing processes. A cGMP facility follows current good manufacturing practice regulations established and enforced by the Food and Drug Administration (FDA), ensuring the quality of drugs, medical devices and blood.
Here, in coordination with enterprise-wide biomanufacturing activities, a Mayo Clinic cGMP laboratory will focus on manufacturing allogenic (donor-derived), engineered, and automated regenerative medicine products. The testing and optimizing of automation in biomanufacturing will lead to scale up of regenerative products in order to produce better, safe and cost-effect products, such as engineered allogenic mesenchymal (adult) stem cells.
Studies have already been done to advance the cell therapy space through identification of suitable donors, ideal tissue sources, the optimized bioreactor conditions and novel methodology for cell administration.
The new cGMP facility is expected to be fully operational by the end of 2020; however, clinical trials are already underway in another area of the campus and being used to develop new technologies which will continue to be researched and scaled up in the new facility.
“Once the facility is up and running in the new building, we’ll be able to immediately expand the current clinical trials,” says Dr. Zubair. “Then it’s time to take these technologies and develop them in a way in which we can get them to patients safely and quickly.”
The Life Sciences Incubator, within the Discovery and Innovation Building will commercialize discoveries from within the Mayo Clinic research labs and seeks to bring them to market quickly. It will also host life sciences companies from across the United States and around the world that could benefit from being co-located with Mayo Clinic resources on the Mayo campus.
“Expansion of our automation and cytoengineering capabilities in the Discovery and Innovation Building further positions Mayo Clinic as a trusted center of excellence in the regenerative medicine space,” says Atta Behfar, M.D., Ph.D., deputy director of translation for the Center for Regenerative Medicine across Mayo Clinic. “This transformative effort in Florida will allow development of novel therapies for patients who connect with us for hope and healing.”
Each Mayo Clinic campus has a unique set of regenerative medicine capabilities researching innovative solutions for patients. Together they form the Center for Regenerative Medicine, working as a whole to create new solutions to transform medicine and surgery.
The liver has the
greatest regenerative capacity of any organ in the body. However, when the
liver is injured beyond its ability to regenerate itself, and a transplant is
not readily available, there are few options for patients.
Led by Scott Nyberg, M.D., Ph.D., researchers are refining their own version of a bioartificial liver, known as the Spheroid Reservoir Bioartificial Liver (SRBAL). This device contains pig liver cell (hepatocyte) spheroids, which replace a patient’s liver function.
artificial liver would bridge the gap until a donor liver becomes available or
if it could help the patient avoid the need for a transplant altogether,” says
While the artificial
liver device has been successfully
demonstrated on pigs with acute liver failure, the ultimate
goal is the bedside treatment of patients in liver failure. With aresearch grant from
Regenerative Medicine Minnesota, Dr. Nyberg and his team are continuing to
study whether the artificial liver could function similar to a kidney dialysis
machine. The patient would be connected to the device, and much like dialysis,
the artificial organ would, perform critical bodily functions while the liver
heals and regenerates.
“The results of our
third large animal study were published in January 2019,”
says Dr. Nyberg. “Pigs were chosen for the early studies because their
metabolism is similar to ours and because they could provide an abundant supply
of liver cells.”
In the treatment
group, all of the animals survived the therapy and were up walking around with
recovered livers at the end of the study. The results have paved the way for
future clinical trials.
Although the SRBAL is
similar to kidney dialysis, the liver is more complicated. It does metabolic
activities, detoxifies wastes, and synthesizes proteins. Because of this, the
SRBAL incorporates living cells– in this case, from pig livers – to carry out
such vital functions for a patient.
“We’re ready for to
move into Phase I trials in humans,” says Dr. Nyberg. “However, funding a
medical device trial using living cells in humans is quite expensive, and we’ll
need to build a new clinically acceptable SRBAL suitable for human use.”
Once funding is
established and the new device developed, the first study in humans would be a
Phase I safety study to make sure the machine is safe for use on people. Second
is a dosing study to determine the efficient dose of liver cells to put in the
bioreactor to repair the liver. Once the Phase I and Phase II studies are complete
and encouraging, a Phase III, multicenter randomized study would follow.
“This is an exciting
time for transplant surgery,” says Charles Rosen,
M.D., director of the William J. von Liebig Center for
Transplantation and Clinic Regeneration at Mayo Clinic. “The need for organ
donation is high, and this research couldn’t come at a better time.”
SRBAL would be most
appropriate for patients who have acute liver failure and are awaiting
transplant, experience an overdose of medication, or those who aren’t
candidates for liver transplant.
“There’s a lot of work to be done, but this is a promising solution to the donor organ shortage in some cases” says Dr. Nyberg. “Many acute liver failure patients would have the opportunity to recover, if only they had time for their liver to regenerate and heal.”
The program has launched clinical trials using a patient’s
own stem cells with the goal of strengthening the heart. One of the clinical
trials uses stem cells collected from a baby’s own umbilical cord blood banked
with the program. The stem cells are injected into the baby’s heart during
of three surgeries.
The phase I clinical trial is the first research monitored
by the Food and Drug Administration that demonstrates the potential of
regenerative therapy for HLHS through collecting, processing and injecting
an infant’s own stem cells directly into the heart at the time of surgery.
Stem cell therapy for HLHS is one of several approaches
for Regenerative Medicine is studying that goes beyond disease
management to search for and discover therapies that support the body in
repairing, regenerating and restoring itself to a state of well-being.