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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