Erik Gatenholm first saw a 3D bioprinter in early 2015. His father, Paul, a professor in chemistry and biopolymer technology at Chalmers University of Technology in Gothenburg, had bought one for his department. It cost somewhere in the region of $200,000. “My father was like, ‘This thing can print human organs,’” Gatenholm recalls, still awestruck. “I said, ‘Bullshit!’ Then it printed a little piece of cartilage. It wasn’t cartilage, but it was like, this could be cartilage. That was the moment when it was like, ‘This is frickin’ cool!’”
Gatenholm, who had long owned a regular 3D printer, decided then that he wanted to do something in 3D bioprinting. His language might be a bit Bill Ted – he grew up between Sweden and the US, where his father is a visiting professor – but his intent and ambitions are very serious. Gatenholm had started his first biotech company aged 18 and he realised that if this machine had the potential to print organs, like his father said, then it had the potential to radically change the world of medicine.
There is a global shortage of organs available for lifesaving transplants. In the UK, for example, you can now expect to wait an average of 944 days – more than two-and-a-half years – for a kidney transplant on the NHS. There’s a similar shortage of liver, lungs and other organs. The lack of transplant tissues is estimated to be the leading cause of death in America. Around 900,000 deaths a year, or around one-third of all deaths in the US, could be prevented or delayed by organ or engineered tissue transplants. The demand, simply, is endless.
Gatenholm’s father introduced him to Héctor Martínez, one of his students who was doing a PhD on tissue engineering, and early on another student, Ivan Tournier, was also involved in the brainstorming. “We were talking about doing some experiments,” says Gatenholm, who is 27, tall and handsome even by Swedish standards.
“So I said, ‘Why don’t we just go online and buy the ink we need?’ And Ivan said, ‘Well, there’s no ink. You can’t buy it.’ And I was like, ‘What do you mean?’ It was the dumbest thing I ever heard. There’s a bunch of printers on the market, just buy the ink. And he said, ‘No, you don’t understand, there is no ink. You have to make it yourself, you have to mix something.’ So I was like, ‘Just make an ink then!’”
Cellink was born from this lightbulb moment in January 2016. Although the technology is the stuff of science fiction, the business principle is classic “razor and blades”. In this model, which is as old as the inventor King Gillette, at the turn of the last century, you practically give away the razor and you make the money on the disposable blades. And repeat, for ever. Or inkjet printers: everyone knows the serious returns are in the replacement ink cartridges.
In bioprinting, Gatenholm and Martínez developed and brought to market the world’s first standardised bioink: it is made primarily from a material called nanocellulose alginate, which is extracted in part from seaweed. If you owned a 3D bioprinter, here, finally, was a product you could effectively buy off the shelf.
The impact of Cellink, especially considering its tender years, has been remarkable. The company has already won a slew of awards: for innovation and entrepreneurialism, as well as the rapturous backing from Sweden’s version of Dragons’ Den. Ten months after its launch, Gatenholm went to the stock market, becoming listed on Nasdaq First North. The initial public offering was oversubscribed by 1,070%.
When I meet Gatenholm in Gothenburg, he still seems to be coming to terms with his company’s newfound liquidity. The office, frankly, is chaotic: there’s an iron on the floor and suit jackets on a peg, in case he’s called on to attend an impromptu client meeting. He and 32-year-old Martínez are working 16-hour days as standard. “The couch is nice to sleep on,” laughs Gatenholm. His office doesn’t actually have anywhere to sit. Cellink is taking on staff so quickly that Gatenholm and Martínez had to give up their chairs to new employees. “We donated them to science,” says Gatenholm wryly.
But Gatenholm is clear: bioprinting’s time is now. “As an entrepreneur, you’re always looking for a blue ocean,” he says. “Entrepreneurs are always asking, ‘Where’s a new area that you become the name of it? And you can claim it?’ I guess I saw bioink and bioprinting to be one of those.”
He shakes his head in disbelief: “No one was doing the ink!”
Bioprinting, as Gatenholm cheerily accepts, is something of a trippy idea and one that raises some ethical concerns. The principles are very similar to conventional 3D printing: you start by using a computer program to make a virtual representation of what you’d like to make and then a printer builds it slice by slice – sometimes around a pre-prepared scaffold – until you have the finished object. But instead of jewellery, little statues or parts for cars, bioprinters offer the potential to create living tissue.
In the beginning, this might mean printing skin or cartilage, which are relatively simple structures and are more straightforward to grow outside the body. Eventually, however, the pioneers of this technology believe they will be able to create complex organs, such as hearts and livers, from scratch. These could then be used in human transplants.
Scientists and commercial companies around the world are working on the project. In fact, something of a race is on. San Diego-based Organovo has been around since 2007 and has had some success in printing parts of lung, kidney and heart muscle. In 2015, it announced a partnership with the cosmetics behemoth L’Oréal on a plan to supply 3D-printed skin. Ultimately, the goal is to eradicate the need for animal trials.
L’Oréal is committing massive resources to bioprinting. In September last year, the company revealed that its scientists were also working with the France-based startup Poietis. The aim this time was to produce synthetic hair follicles. This, it turns out, is devilishly complex: there are more than 15 different cell types in each follicle and there is a cyclical process of fibre production that needs to be stimulated in vitro.
Many have tried, all have failed, but L’Oréal and Poietis are confident they are close to cracking it. The key is the bioprinter that Poietis has developed: most machines push bioink through a nozzle; theirs uses a laser that deposits cells one by one, at a rate of 10,000 drops per second, without damaging the cells. “The way it works is actually quite simple and is similar to inkjet printing,” Fabien Guillemot, the CEO and chief scientific officer of Poietis, explained in the video announcing the collaboration. “It prints 3D structures, in this case, biological tissues, by successively layering microdrops of cells on a surface.”
Poietis calls its innovation 4D bioprinting. “The fourth dimension is time,” said Guillemot. “Because our laser-assisted bioprinting technology can print the cells basically one at a time, it enables us to guide the interaction between the cells and their environment until they produce the biological functions we are looking for.”
In the short to medium term, L’Oréal hopes that its sunscreens and age-defying serums will work more effectively because it can now endlessly test products on a material that reacts exactly like human skin. Perhaps your hair will look more lustrous after using its shampoo, but it’s obvious that the impact of such technology could reach far beyond the cosmetics aisle of the supermarket.
If skin can be printed in a lab, then it’s not a stretch to imagine it being used to treat severe burns. At present, skin grafts, which can lead to bleeding and infection and typically involve a long recovery time, are the most common form of treatment for such burns.
Meanwhile, the developments in synthetic hair follicles appear to open the way for commercial products that reduce hair loss or even implants. “Obviously, our objective for the future is to be able to test innovative molecules using systems of follicles created in vitro,” says José Cotovio, of L’Oréal’s research and innovation department, “but also to increase our understanding of the key processes behind phenomena such as hair ageing, hair loss and hair growth.”
This is just the tip of it – other researchers are working on how to create human organs. “There’s enormous human benefit in bioprinting,” says Gatenholm. “You die because your organs break. That’s why you die. If we can start replacing them, maybe we can extend the human lifespan… That’s really neat!”
We are a little way off from these developments being a reality. But not too far: bioprinted skin could be five years away, thinks Gatenholm. “Within 10 years, we’ll start seeing some implants in the cartilage field, either partial or full,” he says. “Replacement organs, it’s our lifetime.” He adds, smiling: “It’s in our lifetime.”
Already, inevitably, there are some ethical concerns. These range from fears over the quality and the efficacy of artificial skin and implants to the accusation that bioprinting will allow humans to “play God”. Perhaps the most thorough investigation of these issues has been undertaken by a team at the Science, Technology and Innovation Studies department at the University of Edinburgh.
The researchers, led by Dr Niki Vermeulen and Dr Gill Haddow, are unfazed by the horror-movie fantasy of a bioprinted Frankenstein’s monster. “Assuming that God exists, and is someone who can create and influence life, there are already lots of technologies that allow human beings to play God, such as genetics,” says Haddow. “Bioprinting allows people to make small parts of the body and is used for medical applications.”
A much bigger hurdle that 3D bioprinting needs to overcome, they believe, are the costs. Although it is tempting to hope that the ability to make artificial organs will solve the problem of waiting lists, that is unlikely to be the case. “This is an extremely expensive technology that, if it is realised, only a few will be able to afford,” warns Vermeulen. “There is a risk that the health inequalities and postcode lottery that currently exist will also make it unavailable for most people.”
In short, they conclude, the problems and delays that patients experience in the NHS, the US healthcare system and elsewhere “will persist in the context of bioprinting”.
“Ideally, you’d like to think that exporting a relatively cheap bioprinter to a country or region with a non-optimal healthcare structure would enable people to have access to the therapies such a machine could provide. In reality, these printers can only work within an existing healthcare infrastructure that has the capacity to make use of it.”
Cost has certainly been a prohibitive barrier in these early days of 3D bioprinting. The best machines, such as EnvisionTEC’s 3D Bioplotter and RegenHU’s 3DDiscovery, are priced in excess of £150,000 and, as a result, are usually only found in labs at universities. However, here, too, Cellink is keen to shake things up a little. Although it started out supplying bioink, the company soon moved into hardware. On the table next to us in Gatenholm’s office is “Bob”, his pet name for the Inkredible+ 3D bioprinter that Cellink developed and which he carts around trade shows.
The Inkredible+ is an attractive machine: a little smaller than a hotel room minibar, it is clean and white and has blue LEDs. But what really catches the eye is the price. Cellink makes three 3D bioprinters, which cost from just £7,600 to £29,900. The savings, Gatenholm explains, come in part from using cost-effective 3D printer components instead of super-expensive motor rail systems. Also, again in the spirit of the razors and blades business model, Cellink knows that the more people own 3D bioprinters, the more bioink it will sell.
Gatenholm is proud that his company is driving down the costs of 3D bioprinting. While Cellink’s clients include MIT, Harvard and University College London, the company is also making the new technology available to hobbyists. Gatenholm doesn’t know how these people will use their machines and inks – perhaps for printing tissues to test drugs or taking cells from a cancerous tumour and using multiple versions to work out how best to treat it – but that is what makes the new technology so exciting.
“Many of those big bioprinting companies are really pissed off,” says Gatenholm. “But to be honest, the consumers are the ones who drive the market and the consumers want to do this. And for us, I don’t know where the cure for cancer is going to come from. I don’t know if it’s India, or Japan, or South America, or New York, but we want to give everybody a chance to work on it.”
The challenges of printing a human heart
Why would we want to bioprint a heart?
Apart from its geometry, the heart is one of the least complicated organs in the body. It doesn’t perform complicated biochemistry like the liver and kidneys and it is well understood by science, unlike other organs such as the brain. For this reason, the heart could theoretically be one of the easiest organs to bioprint and therefore a good place for the bioprinting industry to start. There are 3,500 people in Europe on the waiting list for a heart transplant, many of whom have needed a new heart for more than two years.
How would you bioprint a heart?
The most promising method could prove to be bioprinted cell scaffolds. Instead of printing layer upon layer of living cells to form a 3D structure, like a conventional 3D printer would do with plastic or metal, the bioprinter would first be used to print a biodegradable scaffold structure of the heart, a kind of skeleton for cells. This scaffold would mimic the heart’s extracellular matrix that provides structural support to cells and helps direct them to where they should be. Heart cells could then be printed into the scaffold, where they would interact and link to form the structure of the heart. After the cells mature into the full structure of the heart, the scaffold could be broken down, leaving a fully functioning heart ready for transplantation. This technique does already exist, albeit on a smaller scale. A scaffold was used to bioprint a small patch of working heart muscle, which was shown to be able to repair a mouse heart that had been damaged by a heart attack.
Why can’t we bioprint a heart already?
Bioprinting a small patch of muscle and bioprinting a whole heart are very different feats. But why is this? There is one problem with creating whole organs that has to be overcome: blood vessels. All blood vessels have proved difficult to create with bioprinting, but creating capillaries, which can be smaller in diameter than the smallest cell, has been nearly impossible. Manufacturing a working vascular system would be such a huge achievement that Nasa is offering a $500,000 prize for the first research team that can do it. The Vascular Tissue Challenge will award the prize for a 1cm thick piece of human tissue with a fully working blood system that can survive for 30 days in vitro.
How far away are we from bioprinting our organs?
Estimates for a date when organ bioprinting will be viable vary wildly, with one team claiming that they will be able to bioprint a heart within six years. No one knows for certain when these techniques will be approved as safe to use for human transplants. However, the sheer number of research scientists working in the 3D bioprinting field, coupled with developments in an industry that is predicted to be worth more than $1.3bn by 2021, means that we can be sure that it isn’t too far away. Agnes Donnelly