Tissue Regeneration
& XenotransplantationANDONG. DARAOAY. PANTUA. SADSAD. YU.
TISSUE ENGINEERING
_ _ _ _ _
ORGAN
_ _ _ _ _ _ _ _
DONATION
TISSUE ENGINEERING
- aims to regenerate damaged tissues by combining cells
from the body with highly porous scaffold biomaterials
- highly multidisciplinary, encompassing the fields of clinical
medicine, mechanical engineering, materials science, and
genetics.
HISTORY &
BACKGROUND
of T.E.
1970s - There were unsuccessful attempts to generate cartilage. It was
determined through these experiments that tissue can be generated by
seeding viable cells in configured scaffolds.
1980s - Dr. Joseph Vacanti came up with the idea of creating artificial
scaffolds. The research of tissue engineering officially began in 1987
1988 - The term ‘tissue engineering’ was officially coined at a National
Science Foundation workshop.
The application of principles and methods of
engineering and life sciences toward the
fundamental understanding of structure-function
relationships in normal and pathological
mammalian tissues and the development of
biological substitutes to restore, maintain or
improve tissue function.
Autograft-transplanting from one
site to another in the
same patient
Allograft- from one
person to another
Problems:
- expensive,painful, constrained
by anatomical limitations
- accessing enough tissue,
risks of rejection, possibility of
introducing infection or
disease
TISSUE ENGINEERING TRIAD
Scaffolds
- act as a template for tissue
formation
- The field relies extensively on the
use of porous 3D scaffolds to
provide the appropriate
environment for the regeneration
of tissues and organs.
Either:
in vitro- to synthesize tissues which can
then be implanted
in vivo- implanted directly into the
injured site, using the body's own
systems, where regeneration of tissues
or organs is induced
Scaffold
Requirements
● Biocompatibility
● Biodegradability
● Mechanical properties
● Scaffold architecture
● Manufacturing technology
● Biomaterial
Biomaterial - ‘material
intended to interface with
biological systems to evaluate,
treat, augment or replace any
tissue, organ or function of the
body’
● Ceramics
● Synthetic polymers
● Natural polymers (collagen)
TISSUE
ENGINEERING:Applications &
Current Research
“Vacanti Mouse”
-Dr. Joseph Vacanti
-ear shaped scaffold with
cartilage cells from a cow
-mouse was power supply
Transplantation of Tissue
Engineered Organs - part of
“Regenerative Medicine”
Skin- Burns and wounds cause
permanent damage
1. Skin grafting
2. Cultured Skin Substitutes
- for those with extensive
wounds or burns
_ _ _ _ _ _ _ _ _
Answer: Cartilage
First Successful Transplantation of Tissue
Engineered Trachea (2011)
○ Recipient: 36 year old man
in Sweden who was
suffering from late stage
tracheal cancer
○ Patient’s own stem cells
grown in bioreactor for 2
days
○ Synthetic scaffolds
First Successful Transplantation of Tissue
Engineered Urethra (2005)
○ Recipients: Five 10-14 year old
boys who suffered injuries due
to accident or illness
○ Cell samples from the boys’
own bladders
○ Custom built biological
scaffolds
○ Patients were evaluated 6
years later in 2011 - all healthy
with functioning urethras
Other tissue engineered organs
○ Blood vessels
○ Bladders
○ Esophagus
○ Muscle
Challenge with “solid organs” such as liver, kidney,
and heart: mix of different types of cells
Tissue engineered
human liver
transplant in mice
○ Will metabolize drugs the
way human livers do
○ Allow scientists to test
toxicity of drugs on mice
Small Intestine
Submucosa (SIS)
as Scaffold
Material from pig’s small
intestine to replace vascular
structures
Contains extracellular matrix -
upon degrading, produces
chemical compounds that
attract stem cells
3D Printing
Scaffolds
○ Produce detailed and
complex scaffolds with
precision
○ Limitations: synthetic
material, material
wastage
Bioprinting ○ 2000s
○ Living cells can be
sprayed through
printer nozzles
○ Researchers have
implanted printed
ears, bones,
cartilage, and
ovaries on animals
CURRENT ISSUES ON TISSUE ENGINEERING
Where everything becomes a tad bit
depressing...
Daedalus and
Icarus
RESEARCH
ETHICS● Will researchers explain clearly what
they will do with the cells and what kind
of tests they will perform?
● Will the information be sufficient?
● Can the human body and its parts be
subject to property rights?
SOCIOECONOMIC
AND POLITICAL
ISSUES
● What will be the cost of tissue
engineering products and treatments?
● Who will finance the research? The
government or the private sector?
● Who will be given priority to receive
these treatments? Young people with
congenital diseases or the elderly who
suffer from degenerative diseases?
ANTHROPOLOGICA
L ISSUES
● Is it ethically right to fight the negative
effects of aging? Is extending life
always a good thing?
● Have we thought about the
consequences of having an aging
society?
● Should we use tissue engineering to
enhance human capabilities?
XENOTRANSPLANTATION
XENOTRANSPLANTATION
- “Xenos” Gk., meaning foreign
- transplant of an nonhuman (animal) organs, tissue or cells
into a human recipients
- driven by the lack of living or deceased donors to supply the
growing demand for transplant
Kidneys – 101,076
Liver – 15,000
Heart – 4,206
Lungs – 1,563
Brain – (everyone who tries to keep up with the
Kardashians)
The Five vital organs essential for survival and the estimated
number of people waiting for transplants. [nanalyze.com]
FACTS & FIGURES
HISTORY
A SHORT TIMELINE AND
MILESTONE OF
XENOTRANSPLANTATION
RESEARCHES
Daedalus and
Icarus
_ _ _ _ _ _ _
_ _ _ _ _ _ _ P R I M A T E
17th Century
19th Century
20th Century
● blood was transfused from various
animal species into patients with a
variety of pathological conditions.
● Skin grafts were carried out from a
variety of animals, with frogs being
the most popular.
● numerous attempts at nonhuman
primate organ transplantation in
patients were carried out
1963
1964
1966
● Reemtsma transplanted chimpanzee
kidneys into 13 patients, one of whom
returned to work for almost 9 months
● The first heart transplant in a human ever
performed was by Hardy, using a
chimpanzee heart, but the patient died
within 2 hours.
● Starzl carried out the first chimpanzee-
to-human liver transplantation
1964
First chimpanzee-human
heart transplant
performed
by James Hardy.
1984
1992
● baboon heart was transplanted into
newborn, ‘Baby Fae’ who had a
hypoplastic left heart syndrome
● Starzl obtained patient survival for 70
days following a baboon liver
transplant.
1984
Baby Fae, the first
infant subject of
xenotransplantation,
sadly, died a month
after.
USES OF XENOTRANSPLANTATION
ORGAN
TRANSPLANT
TISSUE TRANSPLANT
TISSUE
TRANSPLANT
CELL TRANSPLANT
BRIDGING TRANSPLANT
SOLID ORGAN XENOTRANSPLANTATION
Source animal organ ⇒ Human
CELL and TISSUE
XENOTRANSPLANTATION
TYPES OF XENOTRANSPLANTATION
CELL & TISSUE XENOTRANSPLANTATION
Animal Cell/Tissue⇒ HumanWithout any surgical connection
EXTRACORPOREAL PERFUSION
Circulation of Human Blood
outside the bodyThrough animal or bioartificial organ
EXPOSURE TO LIVING
ANIMAL-DERIVED MATERIAL
Human body ⇒ Animal ⇒ Human
PIGSWhy these guys are not
only the source of crispy,
juicy bacon, but a source of
organ for
xenotransplantation...
Great Compatibility
(size and blood type)
Endangered species
Costly to raise & grow slowly to
adulthood
May also harbor unknown
viruses
CHIMPANZEE
BABOON
Similar Anatomy and
Physiology
Small body size
Infrequency of blood
group O (universal donor)
Limited number
PIG
Easy to breed
Similar organ size
Already killed for food
(hence may only raise
fewer ethical concerns
compared to that of using
primates
PIG
More available
Lower risk infections
(versus in nonhuman
primates)ersus nonhuman
Primates)
uh...help
But wait -
HOW DOES IT WORK?
DOES THIS
THING
REALLY
WORK?
Suzanne Ildstad, director of the Institute for Cellular Therapeutics in Louisville, Kentucky
studies bone-marrow transplantation. In 1995 she transplanted baboon bone marrow into a
man named Jeff Getty, who is infected with HIV and has AIDS. Bone marrow produces immune
system cells. The hope was to replace Getty’s crumbling immune system with an HIV-proof
baboon immune system that could protect him from infection. Although the baboon cells
functioned for only two weeks, Getty is still alive and the researchers learned a great deal.
In another experiment, researchers at CytoTherapeutics, Inc., in Lincoln, R.I. implanted cow
adrenal cells—which produce a natural painkiller—into the spinal columns of patient suffering
intractable pain. The cells survived and functioned, but the patients unfortunately felt no pain
relief.
An Immunological Barrier:
HYPERACUTE REJECTION
immune response to cross-
species transplantation
reaction to the “foreign” organ or
cell by the body's normal immune
system
alpha 1,3 galactosyltransferase
(AplhaGal)
HYPERACUTE REJECTION
Revivicor was able to create
genetically modified pigs with
knock-out AlphaGals
Other Immunological Barrier:
Acute Vascular Rejection
Cellular Rejection
Chronic Rejection
CURRENT RESEARCH AND EXAMPLES ON
XENOTRANSPLANTATION
Daedalus and
Icarus
Xenotransplantation had a decline in its researches
due to numbers of earlier unsuccessful attempts
and was revived only when immunosuppressive
drugs became available (Reemtsma, 1995).
Xenotransplantation is still unstable and carries a
high risk of transmitting infectious pathogens.
Treating diabetes with pig islets
Before recombinant human insulin became available, pig islets were used
to treat patients with diabetes. Pig insulin is 98% identical to human
insulin.
Pig islets in microcapsules which allow nutrients to get in and insulin to
get out, and protect the pig islets from the recipient’s immune system so
that no anti-rejection drugs are needed
Problem: xenograft rejection
Immunosuppressive drugs were not enough to prevent an immune response
against the xenografts.
Pigs have molecules on their cell surfaces, including sugars and proteins, that
humans do not have. The immune system recognizes these molecules as non-self
and begins to attack the pig tissue,
Pigs and humans are genetically dissimilar, some of their proteins that serve similar
functions have slight differences that also trigger an immune response.
Solution: Transgenic pigs
2002: scientists generated a genetically modified pig who lacks a sugar
molecule that usually trigger an immune response
Transplants from these transgenic pigs has improved the survival of
xenografts in non-human primates,a pig kidney may last for months, and a
heart can survive for multiple years. However, the primate recipients are
still dependent on immunosuppressive medications to control the immune
rejection.
Solution: Tolerance
approach
Pig bone marrow cells are
administered into the recipient
before the transplantation in
order to trick the immune
system into recognizing the
pig molecules as self
Human organs in animals
Researchers have developed a new technique wherein kidneys from an
aborted human fetus are implanted into a rat to grow to a larger size.
GOAL: Grow human organs in animals
These can also be used to test drugs before human trials to avoid risks
associated with using untested compound in humans.
Vitrification
For long-term storage of xenografts.
Vitrification is the process of converting biological tissue into a low-
temperature glass by rapidly cooling a very high concentration of
cryoprotectants.
CURRENT ISSUES ON XENOTRANSPLANTATION
More depressing...
Daedalus and
Icarus
RELIGION
● Are we playing God?
● Are we going against the teachings of
Islam and Judaism on forbidding the
ingestion of pigs? How about Hinduism
on the sacredness of cows?
PSYCHOSOCIAL
PROBLEMS
● How would you feel if you find out that
the organ donor is from an animal?
● Are the animals treated humanely
during experiments?
© Group 2 MBB 1 2017
END
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