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European Biopharmaceutical Review
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For a number of years now, scientists have conducted research in the
field of regenerative medicine, and their discoveries are very
intriguing. They have learned, for example, that certain animals
regenerate some parts of their bodies. Some lizards can grow back a
severed tail; planarians and sea cucumbers, when cut into two, can each
grow into a new worm; sharks can grow new teeth and replace what was
lost; and starfish can give themselves a new arm.
Discussing
‘the science of regeneration’ at the Whitehead Institute Symposium in
2013, Peter Reddien from Massachusetts Institute of Technology examined
why some animals can regenerate and others cannot. What Reddien and his
research group have found is that adult planarians have pluripotent stem
cells. These cells can make all of the cell types of the animal’s body,
which is why the planarian can regenerate itself. Frogs and
salamanders, however, have tissue-specific stem cells to regenerate a
frog’s tail or a salamander’s limb (1).
Regenerative Models
So
why is it that some animals have pluripotent stem cells and others have
tissue-specific stem cells? Could it be the evolution to a higher
being, which is why pluripotent cells only exist as embryonic cells?
According
to Reddien, the challenge to answering that question is our lack of a
suitable experimental approach – and that new molecular approaches are
needed. He added that the current genetic model system used – involving,
for instance, the mouse, fruit fly and round worm – are great models
when seeking to uncover and understand basic biology, but none of these
animals regenerate. It is regenerating creatures that we need to study.
Reddien
also argued we need animals that are able to regenerate robustly and
quickly, and are easy to grow in the lab. Planarians are a classic
regeneration model in sequencing their genomes and studying the role of
RNA interference. We must develop methods to study both cellular and
molecular mechanisms.
STAP Cells
We have recently
entered into a new era of stem cell research, where stem cells can be
converted to pluripotent cells with the simple methodology of a low pH
bath. Haruko Obokata, a stem cell biologist from RIKEN Center for
Developmental Biology in Japan, found a way to turn stem cells into
pluripotent cells through external stressors (2). Obokata first
discovered this when she “squeezed [cultures cells] through a capillary
tube, [and they] would shrink to a size similar to that of stem cells”.
Five years later, she discovered “three stressors – a bacterial toxin
that perforates the cell membrane, exposure to low pH and physical
squeezing – that each were able to coax the cells to show markers of
pluripotency” (2). Obokata calls this conversion of T cells to
pluripotent cells “stimulus-triggered acquisition of pluripotency
(STAP)”.
“The findings are important to understand nuclear
reprogramming,” says Shinya Yamanaka, who pioneered induced pluripotent
stem cell (iPS) research. “From a practical point of view toward
clinical applications, I see this as a new approach to generate iPS-like
cells” (2).
As with any novel scientific research, this is
creating a lot of buzz and controversy. Robin Lovell-Badge, a stem cell
expert at Britain's National Institute for Medical Research, believes it
will take a while to fully understand the mechanism and capabilities of
the STAP cells and how this translates to medicine. “But the really
intriguing thing to discover will be the mechanism underlying how a low
pH shock triggers reprogramming, and why does it not happen when we eat
lemon or vinegar, or drink cola,” he says (3).
Other Theories
“Regeneration
can also work by causing differentiated cells that had stopped dividing
to ‘go back’ to dividing and multiplying, in order to replace the lost
tissue” (3). Research has shown this phenomenon with regeneration of a
Zebrafish’s heart. The heart muscle cell, called the cardiomyocyte,
divides to replenish missing cardiac tissue, which is why the Zebrafish
has become a powerful organism model (4). This phenomenon was also shown
with a newly born mouse heart, but this property is lost as mice mature
(1). Human beings, like mice, also lose this property as cells mature.
Researchers
at the J. David Gladstone Institutes, affiliates of the University of
California, San Francisco, US, were successful in injecting three genes
inside the damaged region of a mouse heart. Within a month, non-beating
cells that normally form scar tissue had converted into beating heart
muscle cells (5).
“We are not necessarily using stem cells, but
we are taking advantage of controlling the fate of cells and
reprogramming them into whatever we want,” said Dr Deepak Srivastava,
Director of the US Gladstone Institute of Cardiovascular Disease. The
new technique uses three genes called Gata4, Mef2c and Tbx5m – these are
known to play a role in forming and developing the heart, and have
proved successful in lab mice.
3D Printing
The
most advanced progress that scientists have made with regeneration –
although somewhat manmade – is with 3D printing technology. Scientists
using stem cells and/or various forms of scaffolding have taken
advantage of these technologies in a very short period of time, and many
different human parts have been reproduced: skin, ears, nose, eyes,
bone, parts of a skull patch and blood vessels (6).
The idea of
making human parts is not new – indeed, prosthetics have been featured
throughout history, with major advances in recent decades. However, the
production of prosthetics requires artistic ability and is labour- and
time-intensive, often taking months to manufacture. Now, with 3D
printing, one can make these prosthetics in a fraction of the time, with
details that can be easily customised.
Producing human-like eyes
can be more complex. An innovative method, developed by Liz Gill at
Manchester Metropolitan University, UK, with the support of technology
collaborators, offers “the ability to rapidly manufacture (ocular-eye)
prosthesis, capable of clinical chair side modification, to meet a
patient’s individual requirements at a fraction of the cost of current
production methods” (7).
Having a human-like eye for those who
have lost complete sight and need an ocular prosthesis can increase
their quality of life and employability, particularly those in
developing countries who cannot afford prosthetics. Substitute ink with
human stem cells and one can also print skin for burn victims, or even
human cartilage. As a result, scientists and companies worldwide are
racing to develop 3D printed products for uses in medicine.
Recent Developments
Scientists
at the Wake Forest Institute for Regenerative Medicine in the US have
created a hybrid 3D printer that can create implantable human cartilage.
“Once the fake cartilage is implanted, it can form a porous structure
that encourages healthy, natural cartilage to grow around it” (8).
TeVido
BioDevices LLC, a start-up company in Texas, US, is using 3D printing
technology to develop a process to fabricate women’s breast tissue using
the patient’s fat cells. However, the company still has many challenges
to overcome before this goes to market. “Keeping the shape intact,
determining the ideal density of capillaries to maintain blood flow to
all the cells, and preventing cells from dying before implantation are
all key concerns that the company is exploring” (9).
Printing
blood vessels is difficult, because one needs to create a functioning
circulatory system to go with it, stated Günter Tovar, a German
scientist who heads up the Fraunhofer Institute for Interfacial
Engineering and Biotechnology. He points out that “the lining is
important to make sure that the components of the blood do not stick,
but are transported onwards” (10). The printed vessel has to work just
like a normal vessel in directing nutrients to their destination. Tovar –
lead investigator for a 3D-printed blood vessels project called BioRap –
is developing blood vessels with a mix of synthetic polymers and
biomolecules.
Printing organs is harder still, because of their more complex architecture. There are two main reasons for this:
- There
are no adult human stem cells available for the heart or nerves of the
spinal cord, so embryonic or induced pluripotent stem cells must be
used, according to Kevin Shakesheff from University of Nottingham, UK
- Because
organs come in different sizes, it is necessary to guarantee that the
cells are in the right position (6). The ultimate goal is to use these
blood vessels for procedures such as bypass surgery
Professor
Xu Mingen from Hangzhou Normal University: School of Medicine in China
has been able to print a 3D living kidney. Xu explained that stem cells
and a hydrogel mixture are used because the hydrogel is rich in water
and nutrients, and the cells which have blood vessels need tissue space
to grow (11).
The 3D kidney can function like a human kidney in
terms of breaking down toxins and metabolites, and can live for up to
four hours. The ultimate goal is to use the 3D printed kidneys for organ
transplant, with a decreased chance of organ rejection. However, there
are still many years of research ahead before this will be realised.
Other Medical Uses
Other
companies exploring uses for 3D printing in medicine include Organovo
in San Diego, US, where scientists have, for the very first time, been
able to print a tiny 3D replica of a human liver (12).
The mini
liver, which is half a millimeter deep and four millimeters wide, can
perform most of the same functions as a human version. The company’s
immediate goal is to test how it reacts to certain drugs for future
toxicity screening tests and study disease progression, and ultimately
for organ transplant.
Surgeons from a number of different
subspecialties are taking advantage of organs created by way of 3D
printing into their practices. Mark Ginsberg, a US jewellery store owner
and manufacturer, has partnered with surgeons to build organs, such as a
heart, from computed tomography scans (13).
In collaboration
with cardiologists Yoav Dori and Mark Fogel and cardiac surgeons,
doctors at the Children’s Hospital of Philadelphia, US, are printing
replicas of a children’s heart to plan and practice complex surgical
procedures. Congenital heart defects – the most common type of birth
defect in the US – can be complicated and diverse, and can range in
severity from a small hole between chambers to the absence of entire
chambers. Being able to plan and practice surgery with 3D models can
make the procedures faster, resulting in better outcomes (14).
At
Newcastle Upon Tyne Hospitals NHS Trust in the UK, Craig Gerrand, a
consultant orthopedic surgeon, used the hospital’s 3D printer to
fabricate a replacement pelvis out of titanium powder fused together
with a laser (15). The patient had a rare form of bone cancer where most
of the bone had to be removed, which prevented the surgeon from
attaching an implant. The titanium pelvis is coated with a mineral onto
which new bone can grow, and was implanted using a standard hip
replacement.
Closing Thoughts
We could not have
come this far today with 3D printing if it were not for advances in
technology, and also by incorporating technologies from other
disciplines, such as high tech, semiconductor and biofabrication. These
advances also apply to instrumentation for genome sequencing and
high-throughput screening to help us further understand regeneration.
From
this vantage point, it appears that the sky is the limit as to what we
can do in medicine with the help of 3D printing. Combine the theories of
robotics and substitute the metal parts with biofabrication or
bioprinting of bone, cartilage and blood vessels – plus the help of a
microchip – and we may one day be able to print a fully functional arm
or leg, or help grow the necessary part to attach a 3D printed limb.
Nevertheless,
we still have a way to go before we can create a fully functional organ
from 3D printing where rejection rates are low, the organ functions for
an extended period of time and, for paediatric use, the organ can grow
larger.
Might we solve the mystery of regeneration for humans
within a generation of two? It is hard to tell, but the future is
looking very bright.
References
1. Tanaka E, Regeneration:
what does it mean and how does it work, Eurostemcell, 18th October 2011.
Visit: www.eurostemcell.org/ factsheet/regeneration-what-does-itmean-
and-how-does-it-work
2. Cyranoski D, Acid bath offers easy path to
stem cells, Nature 505(7,485): p596, January 2014. Visit: www.nature.
com/news/acid-bath-offers-easypath- to-stem-cells-1.14600
3. Kelland
K, Scientists hail breakthrough in embryonic-like stem cells, Reuters,
29th January 2014. Visit: www.reuters.
com/article/2014/01/29/us-stemcellsidusbrea0s0um20140129
4. Gurley KA and Alvardo AS, Stem cells in animal models of regeneration, Stembook, 2008. Visit: www.stembook. org/node/533
5.
Leuty R, Gladstone scientists make beating cardiac cells inside the
heart, San Franscisco Business Times, 18th April 2012. Visit:
www.bizjournals.com/ sanfrancisco/blog/biotech/2012/04/
gladstone-heart-muscle-stem-cells. html?s=print
6.
Campbell-Dollagham K, How 3D printers are cranking out eyes, bones and
blood vessels, Gizmodo, 3rd December 2013. Visit: http://gizmodo.
com/how-doctors-are-printing-bones-eyes- noses-and-blood-1474983505
7.
Gill L, The development of a high-quality, consistent, cost effective
rapid manufacturing process to produce ocular prosthesis, Manchester
Metropolitan University press release, 21st February 2014
8.
Institute of Physics, Cartilage made easy with novel hybrid printer,
Biofabrication, 22nd November 2012. Visit: www.iop.org/news/12/nov/
page_58984.html
9. Brownlow R, Startup: 3-D printer can create
breast tissue, Austin Business Journal, 10th June 2013. Visit: www.
bizjournals.com/austin/blog/abje_ news/2013/06/startup-3-d-printercan-
create-breast.html?s=print
10. Fraunhofer Institute, Blood vessels
from your printer, Fraunhofer- Gesellschaft press release, 13th
September 2011. Visit: www.igb.
fraunhofer.de/en/press-media/pressreleases/
2011/blood-vessels-from-your- printer.html
11. China View, Living
kidneys 3D printed in China, Medical Design Technology, 9th September
2013. Visit: www.mdtmag.com/ videos/2013/09/living-kidneys-3dprinted-
china
12. Fienberg A, Scientists have 3D-printed mini human livers
for the first time ever, Gizmodo, 23rd April 2013. Visit:
http://gizmodo. com/5995271/scientists-have-
3d+printed-mini-human-liversfor- the-first-time-ever
13. Blanchard
K, 3D printing help surgeons hone skills for real-life surgery, Digital
Journal, 7th July 2013. Visit: http://digitaljournal.com/print/
article/353906#ixzz2qgfkqpor
14. Meeri K, Using 3D printing to treat
children's heart defects, The Inquirer, 10th February 2014. Visit:
http:// articles.philly.com/2014-02-10/ news/47171542_1_heartdefects-
3-d-printer-phoenixchildren# dqxusvwbmhyurxat.99
15. Moore G,
Surgeons have implanted a 3-D-printed pelvis into a UK cancer patient,
FierceMedicalDevices, 11th February 2014. Visit:
www.fiercemedicaldevices. com/story/surgeons-have-implanted-
3-d-printed-pelvis-ukcancer- patient/2014-02-11?utm_
medium=nl&utm_source=internal
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