Download Institute for Regenerative Medicine

Institute for
Regenerative Medicine
SCIENCE FICTION BECOMING SCIENCE FACT
IMAGINE A DAY WHEN CHRONIC DISEASES ARE
TREATED WITH AN INJECTION OF CELLS . . .
WHEN FUNCTIONING NERVES ARE AVAILABLE TO
REPLACE THOSE DAMAGED BY INJURY . . .
WHEN DISEASED ORGANS ARE ROUTINELY
EXCHANGED WITH HEALTHY REPLACEMENTS
GROWN IN LABORATORIES.
Sound like science fiction? Researchers at the Wake Forest Institute
for Regenerative Medicine are hard at work to make this future
a reality. This team was the first in the world to engineer human
organs in the laboratory that were successfully implanted in patients.
Today, these groundbreaking scientists are applying their expertise
to develop cell therapies and replacement tissues and organs for
more than 30 different areas of the body.
This team — driven by the urgent needs of patients all over the
world — is uniquely positioned to make exponential leaps in the
development of regenerative medicine therapies for many disease
conditions. With a history of success and a focused strategy to get
therapies as quickly as possible to patients, the Wake Forest Institute
for Regenerative Medicine is the premier research center of its kind.
Wake Forest Institute for Regenerative Medicine
Positioned for Success
Broad Capabilities
With experts in molecular biology, genetics, cell biology, physiology, pharmacology,
biomaterials, imaging and nanotechnology, the institute has broad research capabilities.
This expertise — combined with a leading-edge facility and research infrastructure that are
unsurpassed — enables the institute to focus on multiple areas of regenerative medicine.
►Tissue Engineering – Growing replacement tissue and organs in the lab. Because a patient’s
own cells are used, there are no issues with rejection.
►Cell Therapies – Using living cells to promote healing and regeneration from within.
►Organoregenesis – Rather than relying
on cells alone, various strategies are
used to promote regeneration, including
biomaterials to aid in cell recruitment
and proteins and molecules to trigger a
regenerative effect.
With its broad research capabilities,
the institute pursues multiple strategies
simultaneously in the quest to quickly identify
the optimal treatment for a particular condition
and get new therapies to patients. For example,
working to find a solution for the 400,000 U.S.
patients on dialysis because of kidney failure,
institute teams are pursuing a cell therapy for
kidney failure, using a 3-D bioprinter to build
replacement organs, and using rejected donor
organs as a platform for engineering matching
organs for patients.
THE INSTITUTE HAS A SUPPORT
INFRASTRUCTURE DESIGNED TO
ACCELERATE THE TRANSLATION OF
SCIENTIFIC DISCOVERIES TO THERAPIES
THAT CAN BENEFIT PATIENTS.
Research Infrastructure
In addition to its talented scientists, the institute
has a support infrastructure designed to
accelerate the translation of scientific discoveries
to therapies that can benefit patients.
►Experts in regulatory pathways and in clinical
trial design who can work effectively with
federal agencies.
►A Good Manufacturing Facility (GTP- and
GMP-compliant), equipped to manufacture
replacement tissues and organs, and to
expand cells for cell therapies under guidelines
of the U.S. Food and Drug Administration.
WakeHealth.edu/WFIRM
Our Research: Engineering the
Future of Health Care
Cell and Gene Therapies
Cell and gene therapies are exciting areas of research because of the potential to heal diseased
or damaged tissues rather than to replace them. Cell therapies are already being delivered
for a variety of conditions, and scientists hope to eventually apply them to treat liver disease,
diabetes, neural disorders, renal failure and other chronic conditions. Gene therapy is a
technique for correcting defective genes responsible for disease development. Examples of our
projects in these areas include:
An Alternative to Traditional Hormone Therapy: Although there are medications to
compensate for the loss of female sex hormones, they often aren’t recommended for longterm use because of the increased risk of heart disease and breast cancer. Institute researchers
are working toward a cell- or tissue-based hormone therapy­ — essentially an artificial ovary to
deliver hormones in a more natural manner than drugs. Their strategy involves engineering
ovarian tissue that integrates with the body using the technique of encapsulating ovarian cells
inside a thin membrane that allows oxygen and nutrients to enter, but would prevent the patient
from rejecting the cells. With this approach, functional ovarian tissue from donors would be
used to engineer bioartificial ovaries for women with impaired ovarian function.
Hemophilia: There is currently no cure for hemophilia A, the most common inheritable
coagulation disorder that causes prolonged bleeding after an injury and can result in joint and
organ damage and life-threatening
internal bleeding. Institute researchers
are exploring a combined cell and gene
therapy for the disorder. Their strategy
is to engineer mesenchymal stem
cells, which have the ability to migrate
to sites of injury and inflammation,
to produce high levels of factor VIII,
the clotting protein missing in people
with hemophilia. The cells — acting
as a carrier for the gene — would then
be transplanted into the patient. In an
animal model of hemophilia A, the
treatment stopped ongoing bleeding
and existing joint damage was reversed.
An Injectible Therapy for Incontinence:
A potential new therapy for urinary
incontinence in women, developed by institute scientists, will soon be evaluated in a clinical
study. Millions of women are affected by the accidental leakage of urine, such as when
they sneeze or cough. The treatment involves taking a small sample of muscle tissue from
patients — growing the cells in the lab — and then injecting the patient’s own muscle cells
into the urinary sphincter, the circular muscle that controls urine flow. The treatment has been
successful in animal studies and the clinical study will test its effectiveness in women.
Wake Forest Institute for Regenerative Medicine
Kidney Disease: The concept of using stem cells to treat
chronic kidney disease is an active area of investigation
internationally. One group has published promising results
using a type of stem cell discovered by institute scientists.
The cells, found in placenta (afterbirth) and amniotic fluid,
are readily available and have been shown to have healing
properties. In animal studies, the treatment delayed kidney
scarring and ameliorated the decline in kidney function.
The investigators concluded that treatment with amniotic
fluid stem cells may be beneficial in kidney diseases
characterized by progressive renal fibrosis.
INSTITUTE SCIENTISTS
ARE EMPLOYING A
VARIETY OF INNOVATIVE
STRATEGIES TO EXPAND
THE NUMBER OF
ENGINEERED TISSUES
AND ORGANS AVAILABLE
FOR TRANSPLANT.
Replacement Tissues and Organs
Worldwide, regenerative medicine scientists have successfully built and implanted replacement
tissues and organs at several levels of complexity, starting with flat structures such as skin.
Tubular structures, including blood vessels, trachea (windpipes) and urethras (urine tubes) have
been implanted in humans, as has a hollow structure, the bladder. Today, the “holy grail” for
tissue engineers is solid organs, such as the liver, kidney, heart and pancreas. Institute scientists
are employing a variety of innovative strategies to expand the number of engineered tissues
and organs available for transplant. Examples of our projects are:
Livers: An institute research team reached an early, but important, milestone in the quest
to grow replacement human livers when it used human liver cells to successfully engineer
miniature livers that function — at least in a laboratory setting — like human livers. Currently,
the team is working to optimize the bioengineering process to support self-organization of the
liver tissue and exploring whether bioengineered livers of human-relevant sizes will continue
to function after transplantation in an animal model. In addition to providing a solution to the
shortage of donor livers available for patients who need transplants, laboratory-engineered
livers could also be used to test the safety of new drugs.
WakeHealth.edu/WFIRM
Blood Vessels: Lab-grown
blood vessels could be used in
a variety of applications — from
heart bypass surgery to dialysis
access in patients whose
own vessels are diseased.
Institute scientists were the
first in the world to engineer
functional blood vessels that
were implanted preclinically
and survived long term. Their
strategy is to collect a type
of stem cell from a patient’s
blood and extract endothelial
cells (the cells that line blood
vessels and prevent clots) that
can be multiplied in the lab. Once there are enough cells, the cells are placed on a
scaffold and the engineered vessel is placed in a bioreactor system to acclimate it
to the conditions of the body.
Engineered Eggs for Infertile Women: Several fertility disorders can leave
premenopausal women without enough eggs to become pregnant. Institute
researchers moved a step closer to addressing this problem when, in a rat model, they
successfully stimulated the production of ovarian cells that matured into early-stage eggs
that could potentially be fertilized. The goal of this project is to use a woman’s own ovarian
cells to grow eggs in the laboratory that could be implanted in the patient or used for in vitro
fertilization procedures.
Kidneys: There is a critical shortage of organs for transplantation, with more than 60,000
people on the nationwide waiting list. Institute scientists are tackling the problem from several
different fronts. Building on their earlier research in which a mini-kidney created from cells
and biomaterials functioned short term in a steer, institute scientists are using bioprinting
technology to print experimental 3-D kidney prototypes. Another team is focused
on “recycling” donor organs — either pig kidneys or human kidneys rejected
for transplant. The idea is to use these organs as a platform to engineer
patient-specific replacement organs.
Wake Forest Institute for Regenerative Medicine
Anal Sphincters: Institute researchers built the first anal sphincters that function in animals,
suggesting a potential future treatment for both fecal and urinary incontinence. Made from
muscle and nerve cells, the sphincters developed a blood supply and maintained function when
implanted in mice. This is the first bioengineered sphincter made with both muscle and nerve
cells, making it “pre-wired” for placement in the body. There is a high incidence of weakened
internal fecal sphincters in older adults; women who have had episiotomies during childbirth
can also be affected.
Muscle: Lab-engineered replacement muscle could help patients with defects due to cleft
lip and palate and traumatic injuries or surgery. In animal studies, institute scientists have
successfully engineered muscle tissue that resulted in functional recovery. The process involves
“exercising” engineered constructs on a computer-controlled device before implantation. The
research scientists are expanding their work to build muscle of almost any structural shape and
to promote nerve function until existing nerves can grow to meet implanted muscle tissue.
Organ Regeneration
Regenerating an organ from within the body may be possible through tactics such as injecting
chemicals to stimulate stem cells to go to an injury site and promote repair. Another option is
to pre-treat cell-less scaffolds with chemicals to attract stem cells. An example is a self-seeding
heart valve. In animal studies, a pig valve with all cells removed — commonly used in human
valve replacements today — was coated with a chemical to attract endothelial cells. With
the addition of cells, the valve can become a living structure and less likely to degrade and
need replacing. In a short-term, preclinical study, scientists saw the formation of normal valve
architecture within a few months.
WakeHealth.edu/WFIRM
Support Technologies: Making
Regenerative Medicine a Reality
Developing regenerative medicine therapies
requires more than advanced knowledge about
cells and biomaterials. There are numerous
associated challenges to overcome. How will organ
constructs be supplied with oxygen until they
integrate with the body? How can the precision
of cell placement be controlled in multi-celled
constructs? Institute scientists have developed
an array of support technologies that are proving
invaluable in translating the science of regenerative
medicine into therapies that can benefit patients.
INSTITUTE SCIENTISTS HAVE
DEVELOPED AN ARRAY OF
SUPPORT TECHNOLOGIES THAT
ARE PROVING INVALUABLE IN
TRANSLATING THE SCIENCE
OF REGENERATIVE MEDICINE
INTO THERAPIES THAT
CAN BENEFIT PATIENTS.
Oxygen Generating Particles: Institute scientists are using safe, natural chemicals that
generate oxygen in a variety of projects — from a treatment to promote limb salvage to
incorporating the particles into organ scaffolds. With limb salvage, the particles, in the form
of an injectable gel, could potentially slow muscle death until a surgeon could intervene and
restore the blood supply. When used in scaffold construction, the particles would help keep the
engineered organ alive until the body’s blood vessels could grow to reach it.
Bioprinting: Can replacement organs one day come from a printer? That’s the ultimate goal of
the institute’s bioprinting program. Complex tissues are composed of many cell types that are
arranged in a very specific order. It’s the precision of bioprinting that makes it such an attractive
option for bioengineering organs. Institute scientists are leaders in designing and building
printers for medical applications. For example, a machine that prints skin cells has the potential
to provide quick coverage for burn victims, hopefully increasing chances of survival and offering
an alternative to painful skin grafts.
A 3-D printer — which has the capacity to layer cells and biomaterials to form almost any
shape — is being evaluated in projects ranging from cartilage and skin to kidney prototypes.
With this device, patient data, such as from a CT scan, is used to create a computer model of
the organ to be printed. This computer model is used to guide the printer as it layer-by-layer
prints a 3-D structure made up of cells and the biomaterials to hold the cells together.
Wake Forest Institute for Regenerative Medicine
Bioreactors: Research has shown that when certain organs and tissues are bioengineered in the
lab, a period of “exercise” or “preconditioning” can increase function. When a blood vessel is
coated with cells, for example, immediate implantation in the body could result in the cells being
washed away. But by first conditioning the vessels in a system that mimics bloods flow, force can
be gradually increased, so the vessel can acclimate to its job. Bioreactor systems that mimic the
body’s natural conditions are also used when cells are introduced into complex organs, such
as the liver. Institute scientists have built tailored systems to precondition or seed a variety of
engineered tissues and organs, from heart valves and blood vessels to livers and kidneys.
Imaging: Being able to decode the regenerative process at the molecular and cellular level
and visualize it in real time would allow scientists to optimize their techniques and build better
tissues. In addition, a better understanding of the regenerative process could enable scientists
to prompt regeneration in many types of tissue. Imaging projects at the institute include:
►A fiber-optic based imaging system is being applied to study the maturation of
bioengineered blood vessels and other tissues in collaboration with Virginia Tech. Unlike a
conventional microscope that can only view tissues by directly looking at them, this system
allows remote imaging that can provide real-time information on the engineered constructs.
The approach involves embedding
micro-imaging channels into the
scaffolds and labeling cells on the
scaffold with fluorescent proteins.
An optical fiber inserted into these
channels delivers laser light that allows
scientists to visually track different cell
types on the scaffold.
►A near-infrared imaging system
originally designed to identify tumors
and tumor cells in real time during
surgery is being used to detect
genetically labeled cells in engineered
composite tissues. A contrast agent is
injected into a tissue construct and a
laser pen emitting near-infrared light
allows scientists to detect cells and
create a topographical map of cell
placement. For example, using the
anal sphincter as a model, scientists
are able to see two cell types in their
native environment on the sphincter.
►A project that studies the tumor
microenvironment to better
understand how various cell types
interact with the tumor also has direct applications for regenerative medicine. By following
the idea that “tumors are wounds that never heal,” scientists use mice containing colored
cells, allowing the identification of the stem cells that play a role in tumor formation.
Surprisingly, these same cells also play an important role in wound healing. Using these mice,
scientists can create a “fingerprint” of each cell type and determine the cellular makeup of
implanted engineered tissues and organs.
WakeHealth.edu/WFIRM
A Record of “World Firsts”
ACHIEVEMENTS OF INSTITUTE SCIENTISTS INCLUDE ENGINEERING
REPLACEMENT TISSUES AND ORGANS IN ALL FOUR CATEGORIES: FLAT
STRUCTURES, TUBULAR TISSUES, HOLLOW ORGANS AND SOLID ORGANS.
►First to demonstrate that complex, layered tissue structures can be engineered using
cells. (1994)
► Developed the first tissue-engineered product to go to the U.S. Food and Drug Administration
for Phase 1 approval for clinical applications, consisting of cells and biomaterials for
injectable therapy. (1995)
►First to use biomaterials alone, without the addition of cells, implanted in patients for the
regeneration of organs. (1996)
►First to create a laboratory-grown organ — engineered bladder tissue (hollow organ) that was
successfully implanted in patients. (1999)
►First to create a functional solid organ
experimentally, a miniature kidney
that secretes urine. (2003)
►Led the team that engineered tubular
organs (urine conduits) and implanted
them in patients. (2004)
► Founded the Regenerative Medicine
Foundation, a non-profit organization
dedicated to the advancement of
regenerative medicine treatments
and therapies. (2005)
►Identified and characterized a new
source of stem cells derived from
amniotic fluid and placenta, which
show promise for the treatment of
many diseases. (2007)
►Selected to co-lead the Armed Forces
Institute of Regenerative Medicine,
an $85 million, federally funded effort
to apply regenerative medicine to
battlefield injuries. (2008)
►First to engineer functional
experimental solid organs (penile
erectile tissue and mini-livers) using a strategy to recycle donor organs, with potential
applications to other solid organs, such as the kidney and pancreas. (2009 and 2010)
►Built the first anal sphincters that function in animals, suggesting a potential future treatment
for both fecal and urinary incontinence. (2011)
►Selected to lead the second phase of the Armed Forces Institute of Regenerative Medicine,
a $75 million project. (2014)
Wake Forest Institute for Regenerative Medicine
Leading National
Research Efforts
As one of the world’s premier regenerative medicine centers,
the institute has been selected to lead two significant,
federally funded projects:
Body on a Chip: A unique $24 million project funded by
the Space and Naval Warfare Systems Center Pacific aims
to build a system of miniaturized human organs to model
both the body’s response to harmful agents and potential
therapies. This approach will better model the response
of humans to drugs and reduce the need for testing in
animals. The ultimate goal is to use the system to develop
countermeasures to chemical and biological attacks.
THE INSTITUTE HAS
BEEN SELECTED TO
LEAD TWO SIGNIFICANT,
FEDERALLY FUNDED
PROJECTS.
Armed Forces Institute for Regenerative Medicine (AFIRM): The institute, which co-led the
original AFIRM, was selected to lead the second phase of the grant. This $75 million project,
funded by the Department of Defense and the National Institutes of Health, works to apply
regenerative medicine to battlefield injuries. Projects include restoring function to severely
traumatized limbs, reconstruction for facial and skull injuries through tissue regeneration, skin
regeneration for burn injuries, new treatments to prevent rejection of “composite” transplants
such as face and hands, and reconstruction of the genitourinary/lower abdomen including the
bladder, anal sphincter and external genitalia.
WakeHealth.edu/WFIRM
SCIENCE FICTION BECOMING SCIENCE FACT
WakeHealth.edu/WFIRM
Worldwide Collaborations
Because the need for replacement organs and tissues is
so great — and is worldwide — one of the institute’s most
important missions is collaborating with researchers around
the globe. This approach, which offers the greatest chance
of success, has resulted in partnerships such as:
Austria: Ludwig Boltzmann Institute, Wien
China: Beihang University, Beihang; State Key Laboratory for
Neuroregeneration, Nantong University, Nantong; Shanghai Tissue
Engineering Research Center, Jiao Tong University School of Medicine, Shanghai; Jiangsu Key
Laboratory of Neuroregeneration, Nantong University
Egypt: Kasr Al Ainy Teaching Hospital, Cairo University; El Manial Assuit University, Assuit
Germany: Aachen University Institute of Applied Medical Engineering, Aachen;
European Center for Medical Technologies and Applications, Cologne; Institute for Tissue
Engineering and Regenerative Medicine, Lukas Hospital, Neuss
Hungary: University of Szeged Institute of Surgical Research, Szeged
Ireland: National University of Ireland at Galway and Regenerative Medicine Institute of
Ireland at Galway
Israel: Rambam Medical Center, Haifa
Japan: Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s
Medical University
Korea: Kyungpook National University and Kyungpook National University Hospital Daegu;
Korea Institute of Science and Technology, Seoul
Russia: First Moscow State Medical University, Moscow
Switzerland: University Hospital Basel, ICFS, Basel
Taiwan: Taipei Medical University, Taipei
Closer to home, the institute has more than 200 national collaborations with approximately 60
universities, with several strategic partnerships:
► Collaborations with veterinary schools at Virginia Tech and N.C. State University have the potential
to benefit companion animals and to accelerate the development of new therapies for humans.
►Institute scientists work with N.C. State University’s Edward P. Fitts Department of Industrial and
Systems Engineering to apply the processes used to bring automation, quality and efficiency to
regenerative medicine.
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