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European Biopharmaceutical Review

A New Dimension

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.

1. Tanaka E, Regeneration: what does it mean and how does it work, Eurostemcell, 18th October 2011. Visit: 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: 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: page_58984.html
9. Brownlow R, Startup: 3-D printer can create breast tissue, Austin Business Journal, 10th June 2013. Visit: www. 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. 2011/blood-vessels-from-your- printer.html
11. China View, Living kidneys 3D printed in China, Medical Design Technology, 9th September 2013. Visit: 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: article/353906#ixzz2qgfkqpor
14. Meeri K, Using 3D printing to treat children's heart defects, The Inquirer, 10th February 2014. Visit: http:// 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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Regina Au is a Strategic Marketing Consultant at BioMarketing Insight, and has more than 20 years of experience in the biotech, pharma, medical device and diagnostic industries. Regina previously held sales and marketing roles at companies such as Merck, Genzyme Corp, NMT Medical and Radi Medical Systems. She has an MBA in Marketing from the University of Connecticut, a Microbiology degree from the University of Michigan and a Masters in International Management from Thunderbird School of Global Management.
Regina Au
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