Posts (168)

3 days ago · A Step Toward Bioengineered Transplantable Livers

Dr. Scott Nyberg picture

More than four million American suffer from chronic end stage liver disease, according to the Centers for Disease Control and Prevention, and a liver transplant can mean the difference between life and death for some patients. However, livers are in short supply, and the number of people awaiting new livers far exceeds the number of donor livers available.

To address
the acute shortage of donor livers, Mayo
Clinic Center for Regenerative Medicine
has prioritized developing
bioengineered transplantable human livers. Early research published in the
October 14 edition of Nature Biomedical Engineering demonstrates for the first time, that
a clinically relevant tissue-engineered liver graft implanted in pigs shows
indications of vascular function similar to a normal donor liver. The research
solves a critical first step in bioengineering transplantable livers and could
accelerate development of bioengineered organs as a viable alternative to donor
organs.

In order to
develop the implantable graph, the pig liver is decellularized – a process
which removes all of the cells from the liver. This creates an empty structure,
called a bio-scaffold with the original architecture, mechanical properties and
vascular network of a normal liver. The bio-scaffold is recellularized with
cell types necessary to restore normal function and blood flow, in this case
endothelial cells.

“Our
research discovered that liver cells in the graft show signs of regeneration
like a normal liver. The endothelial cells that line blood vessels change their
appearance and become liver-like so no anti-coagulation is needed to prevent
clotting of the graft,” says Scott Nyberg, M.D., Ph.D., final author on the paper. “This
discovery gives hope that solutions to the organ shortage are on the horizon.”

At this
stage of the research, the native livers are left in similar to kidney
transplants and the graphs are recelluarized with only endothelial cells. The
next step will be to use both endothelial cells and hepatocytes (liver cells)
and remove the native liver to allow for clinically correct placement of the
bioengineered liver.

Mayo
Clinic’s research in pigs is preliminary, and is not yet ready for human
studies. The research is a collaboration between Mayo Clinic and Miromatrix
Medical to advance  the development of
bioengineered organs.

“The
published work solves a problem, essentially to ability to create a functional
vasculature that could bring nutrients to the engineered tissue and take away
the waste, that has delayed the advancement of creating advanced tissues and
organs to help treat patients,” says Jeff Ross, Ph.D., CEO of Miromatrix. “Having
solved this issue, we are now performing the next important step of
transplanting bioengineered livers with functional liver cells into pigs, a
critical next step in moving the therapy into the human clinical trials.”

Thu, Oct 10 9:42pm · Regenerative Strategies for Osteoarthritis: Jonathan Finnoff, D.O.

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.

Jonathan
Finnoff, D.O.
, a physical medicine and rehabilitation specialist and medical
director of Mayo Clinic Sports
Medicine
at Mayo Clinic Square in Minneapolis, is leading a study of regenerative
therapies as a treatment option when standard of care procedures do not work.
The study is funded through a Regenerative
Medicine Minnesota research grant
.

“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
option.”

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:

Thu, Sep 26 8:17pm · Regeneration for All

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.

Fri, Sep 20 1:34pm · Biomanufacturing in Discovery Square Building will Bring New Options to Patients

The grand opening of One Discovery Square opens a new
chapter in biomanufacturing focused on connecting patients with complex medical
conditions with novel biotherapeutic solutions.

The Mayo Clinic Center for Regenerative Medicine Advanced
Biomanufacturing facility is one of the Mayo tenants in the building focused on
the acceleration of new health care products to market by partnering innovation
with industry.

When it is fully up and running in One Discovery Square, the
facility will seek to develop first-of-their kind therapeutic products, and
together with industry collaborators, move them quickly from the bench to the
bedside for Mayo patients and then others around the world.   

A new era of regeneration, biomanufacturing harnesses
biomaterials and biomolecules for use in medicine. The resulting new generation
of health care products has the potential to bring new treatment options to
patients.

“In biomanufacturing, technologies have historically come
with significant cost of manufacturing,” says Atta
Behfar, M.D., Ph.D.
, a cardiologist and deputy director of translation for
the Center for Regenerative Medicine. “Forged with the vision of industry
collaboration, the goal for Discovery Square is to establish transformative
biomanufacturing platforms that will ultimately connect patients with
untreatable conditions with accessible curative technologies.”

The Center for Regenerative Medicine Advanced
Biomanufacturing facility is led by Dr. Behfar and Andre
Terzic, M.D., Ph.D.
, the Michael S. and Mary Sue Shannon Director, Mayo
Clinic Center for Regenerative Medicine.

“The effort in One Discovery Square will allow us to forge
an ecosystem of innovation by partnering with industry to establish next
generation regenerative technologies at Mayo Clinic. With a focus on scaled and
targeted biomanufacturing platforms, the acility is poised to establish new
regenerative tools adapted for rapid integration into practice,” says Dr.
Terzic.

Biomanufacturing in
Patient Care

There are many implications of biomanufacturing in health
care. The Mayo Clinic Center for Regenerative Medicine is leading several
efforts that will advance patient care, including:

  • Cellular and gene therapy: These two types of therapies offer therapeutic intervention for a range of diseases for which relatively limited clinical options are currently available. Cellular therapies contain cells or tissues derived either from a donor or a person’s own stem cells that employ healing through replacement of function. Gene therapy is the addition of new genes to a patient’s cell to replace missing or malfunctioning genes that are driving disease.
  • Acellular technology: Acellular — or cell free — technology are biologics that are termed “off-the-shelf.” It means they can be manufactured and stored for long periods of time right at the hospital, as opposed to needing to be frozen, thawed and brought to a patient.  Cell free products are less generally expensive for patients and can be used more widely.
  • Tissue engineering: The goal of tissue engineering is to assemble functional constructs that restore, maintain, or improve damaged tissues or whole organs using scaffolds, cells and biologically active molecules. Tissue engineering uses new approaches to repair, restore or regenerate tissue function lost due to injury, chronic disease and aging.

Biomanufacturing Challenges

One of the challenges in biomanufacturing is having the
proper technology and production capabilities in place to meet rigorous
standards for U.S. Food and Drug Administration (FDA) approval.  A key component of that is the highly
regulated Current Good Manufacturing Practices (cGMP) laboratory needed to
research and produce these new products, such as cellular and acellular
therapies, pharmaceuticals, medical devices, and engineered tissues. The Center
for Regenerative Medicine Advanced Biomanufacturing facility will feature cGMP
lab space, which is important to assure proper design, monitoring, and control
of manufacturing processes and follows cGMP regulations established and
enforced by the FDA.

“One Discovery Square provides a central location to
develop, translate and apply new biologics that are unique to Mayo Clinic,”
says Dr. Behfar.  “Our goal has always
been to get the latest technologies to patients quickly.”

Thu, Sep 12 1:06pm · Researching Stem Cells for Kidney Disease: LaTonya Hickson, M.D.

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:

Thu, Aug 29 8:00am · Gerstner Regenerative Medicine Initiative: Tracking Outcomes and Supporting Clinical Trials

Image of an outcomes registry tablet used during consultations.
Outcomes registry tablet used during consults.

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.

The Gerstner Regenerative
Medicine Initiative, funded through a
grant from The Louis V. Gerstner Jr. Fund at Vanguard Charitable
, is
leading the design and implementation of a regenerative medicine outcomes
registry and supporting ongoing osteoarthritis research and clinical trials at
Mayo Clinic.

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.

Jennifer Arthurs ARNP handing a outcomes registry tablet to a patient
Jennifer Arthurs, ARNP, handing an outcomes registry tablet to a patient.

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:

Thu, Aug 22 11:17am · New Florida Building Dedicated to Medical Discovery and Innovation

Discovery and Innovation Building

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.”

Ex vivo perfusion and ventilation of a donor lung

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.”

Researchers in a cGMP clean room.

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.

Tue, Jul 30 9:32am · Bioartificial Liver: Bridge to Liver Regeneration

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.

Scott Nyberg, M.D., Ph.D.

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.

“Ideally, the
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
Dr. Nyberg.

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 a research 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.

Schematic of the extracorporeal circuit of the Spheroid Reservoir Bioartificial Liver

 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.”

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