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Frankenscience or fearless medicine?
TWO centuries from the debut of Mary Shelley's Frankenstein, science is again testing the boundaries of humanity. The creation of the first commercial three-dimensional (3D) bioprinter would make possible the printing of a human being from scratch, layer by layer, organ by organ, vastly advanced from resurrecting life by piecing together flesh recovered from the dead as pictured in the 1800s literary classic.
So declared a posting on a Shelley fan site,frankensteindiaries.com. At the time of the post, in August 2016, that first commercial 3D bioprinter was already in existence. It was launched in 2009 by two biomedical companies based out of the United States and Australia, Organovo and Invetech. And, in 2014, thousands of miles away in Singapore, home-grown startup Bio3D Technologies laid claim to having invented this Little Red Dot's first 3D bioprinter.
The hype that ensued sent investors flocking to companies like Organovo, while also throwing up the inevitable - and perennial - question of how far modern medical science should press on with saving lives at the risk of ending up playing god. To be fair, Bio3D Tech and Organovo never expressed the intent to pursue Victor Frankenstein's ambition. Instead, they had banked on the promise that 3D bioprinting holds, to eradicate long waiting lists for organ transplants.
There are compelling reasons to do so. Statistics released by the US Department of Health and Human Services estimated that about 20 people die each day while waiting for organ transplants in the US. Yale-NUS College's Jean Liu observed in a commentary published last October that the average patient with organ failure in Singapore has to wait nine to 10 years for a kidney transplant and one to two years for a liver or heart.
It's no surprise, therefore, that institutional investors like BlackRock and several pension funds came to back a 3D bioprinting startup like Organovo. But the initial excitement over bioprinting startups soon fizzled out. In the years following their inception, it became apparent that 3D bioprinting of organs for human transplants would remain a concept on paper for some time to come, not least because it has not won regulatory approval.
Less than five years from its inception, private-owned Bio3D Tech went bust. Nasdaq-listed Organovo, which went public in 2012, took another beating on the stock exchange in early August on posting yet another quarterly loss. Analysts warned that Organovo may exhaust its existing cash before it can secure regulatory approval for the use of liver tissue printed using its technology in medical treatments.
The plight of Organovo and Bio3D Tech, however, has not dented optimism over a still-distant future for 3D bioprinting. Market Research Future forecasted a 25 per cent annualised growth for 3D bioprinting in the years from 2018 through to 2023; Grand View Research Inc projected the global market for the technology may reach US$2.6 billion by 2024. These forecasts prompt another question - how deep is the well of optimism surrounding the promise of 3D printing in the biomedical field, the surge of sentiment which has backed Organovo's several equity raising exercises since 2012 and kept startups going in Singapore after Bio3D Tech folded?
Goh Khoon Seng, CEO of Osteopore International, a 3D-printing pioneer in Singapore's medical technology (medtech) sector, argues that investors and analysts should avoid lumping all biomedical applications together. A distinction should be made between those startups looking at bioprinting from cells and tissues, and others tapping the additive manufacturing technology to create plastic and metal medical devices and anatomic implants, he says.
Today, biomedical-focused players make up the biggest share or 25 per cent of 3D-printing startups here. None of these are involved in bioprinting, data from National Additive Manufacturing Innovation Cluster shows. There are, however, several 3D-printing startups focusing on dental health, restorative repair and semi-permanent or permanent implants.
Findings from US-based consultancy Gartner have shed some light on why that is the case. While 3D printing of hearing devices, for instance, is deemed to have gone mainstream as of July 2017, other biomedical inventions are way behind on the curve. The use of 3D-printed surgical implants is still two to five years to mainstream adoption, while 3D-bioprinted organ transplants have more than 10 years to go.
Going mainstream calls for medical devices to clear regulatory hurdles. This takes more time for devices that have higher risks associated with their uses. But, by and large, 3D printing-focused startups face the challenge of operating in a regulatory environment that's still playing catch-up with technological advances.
Take 3D-printed customised implants. Regulations guiding their use remain hazy, so to get that first big break, startups often have to think out of the box.
One startup founded just two years ago, Supercraft3D, has already supplied 11 titanium implants for orthopedic surgeries carried out or planned for patients in India. Founding CEO Maltesh Somasekharappa explains that these implants have either been used in treatments of patients who have experienced trauma or were diagnosed with cancer; these can proceed once endorsed by ethical committees of hospitals and do not need to seek regulatory clearance.
Mr Somasekharappa says he and his two other co-founders, all trained engineering and financial professionals from India and the US, have pursued the orthopedic path partly because "bone implants, especially those made of titanium ones have been tried and tested in surgeries".
Supercraft3D first started with 3D-printed surgical models to help doctors visualise a patient's anatomy ahead of a surgery. It claims to be able to translate X-ray and other traditional diagnostic images into clear transparent 3D surgical models within 24 hours in most cases.
Mr Somasekharappa says Supercraft3D "envisions the need for 3D-printing application in every aspect of medical treatment" as patients worldwide "seek more customised treatments".
Adding to this is the urgency for the biomedical industry "to keep up with population growth" despite "an acute shortage of doctors worldwide". "In countries like India with a population of 1.3 billion, there just aren't enough doctors. Doctors are under tremendous pressure to deliver and 3D printing can help them to perform surgeries in half the time with better precision," he explains.
The good news is that regulators including the US Food and Drug Administration (FDA) and Australia's Therapeutic Goods Administration (TGA) have already started reviewing the guidelines for medical devices to keep up with the trend towards personalised and customised healthcare. Singapore's Health Sciences Authority (HSA) and the US FDA are also part of a dedicated workgroup under the International Medical Device Regulators Forum, which aims to develop guidelines that may help harmonise regulatory requirements for personalised medical devices.
But 3D printing has disrupted manufacturing of medical devices, which can now take place in hospitals and even residences miles away from the confines of a factory environment.
Considering the disruption to the existing manufacturing value chain, many expect the regulatory framework for 3D printing to remain in a state of flux in the months to come.
Singapore-headquartered Osteopore appears to have found a way to work with the regulatory limits. Established in 1996, Osteopore has already supplied over 10,000 3D-printed surgical implants, as at the end of 2017, that have been used to help heal or reconstruct body parts - skull, teeth and gums, eye orbit, to name a few.
Its implants take the form of a standard microstructure that can be trimmed to fit the needs of the patients. The advent of 3D printing has made possible the creation of such microstructures which need to be printed layer by layer to a precise configuration that traps cells and blood vessels for the purpose of repairing tissues.
As the cells propagate, the microstructure, made of biodegradable polymer, breaks down into carbon dioxide and water and dissolves in the blood stream.
Mr Goh, Osteopore's CEO, says such "standard off-the-shelf devices... constitute 95 per cent of Osteopore's 3D-printed products". The regulatory pathway is "well-defined" for such standard devices, unlike the case for customised devices.
The cost of procedures involving the use of Osteopore's devices may still range widely from S$7,000 to beyond S$100,000 in Singapore, but Mr Goh points to distinct benefits.
The use of Osteopore's biodegradable device to help self-repair of tissue frees time and resources otherwise spent on follow-through check-ups or corrective surgeries needed on permanent or semi-permanent implants. Osteopore will dramatically scale up its operations this year, with the total number of patients receiving its implants projected to double to about 20,000.
But its journey hasn't been all smooth sailing.
Co-founder and NTU Professor Teoh Swee Hin recalls having to defend the merits of using biodegradable polymer in the early years when most implants were made from titanium and other synthetic materials.
With the West being a dominant force in modern medical science, Osteopore also has had to overcome prejudice against inventions originating from Asia. Prof Teoh says Osteopore has managed to gain recognition partly because it has the backing from two universities - Nanyang Technological University (NTU) and National University of Singapore (NUS) - that have climbed the ranks over the past decade. The green light came in 2006, when Osteopore's proprietary microstructure was approved for free sale by the US FDA. This was followed by Singapore's HSA in 2007 and the European Commission's CE-Mark in 2009.
It's a long way from Osteopore's first successful clinical trial in 2002, which saw the implant of its microstructure to help the skull of a 70-year-old Singapore man heal after a brain surgery. More recently, the startup has participated in a shin bone operation that helped an Australian man avert amputation. The implant used was reportedly grown out of the man's own bone and tissue on a 3D scaffold printed using Osteopore's technology.
Going Down Under
Osteopore and many medtech startups have tapped Australia for clinical study opportunities that may not be made available in Singapore or elsewhere. Professor Susan Dodd of the University of New South Wales (UNSW) explains that, in this respect, Australia's regulatory regime grants a clinician "greater latitude to decide on the use of biocompatible 3D-printed implants if no other feasible options are available". It has also helped, Prof Dodd says, that Australia observes the spirit of universal healthcare; this has bolstered confidence that any patients participating in clinical trials would not end up bearing the full risks and costs resulting from any medical mishaps.
She notes an inclination in Australia to consider the use of 3D-printed implants particularly for orthopedic surgeries because like many other countries, it faces the challenge of "maintaining health and mobility of an ageing population in order to maintain the effectiveness of its economy".
Yet, even in Australia, regulators have already indicated the intent to tighten control over the use of 3D-bioprinted implants derived from the manipulation of a patient's own stem cells, or autologous stem cell interventions. The TGA then cited "growing global concern with direct to consumer advertising of unproven autologous stem cell interventions" and "risks to patient safety due to increasing complexity of treatments offered, often for very serious illnesses".
Dr Jeremy Lin, partner and head of health and life sciences practice for Asia-Pacific at Oliver Wyman, argues that 3D-printing use in the biomedical industry should be seen as "moving away from a one-size-fits-all model... to tailoring the treatment to a patient's needs".
But clearly, 3D bioprinting, which would enable treatments tailor-made according to a patient's genetic make-up, is still a long way off.
Thus far, 3D-printing startups here have steered away from bioprinting. Prof Teoh and his fellow co-founders of Osteopore chose to focus on helping the human body to heal. "We will not work on embryos or create another species," the Osteopore co-founder says.
Supercraft3D's Mr Somasekharappa says he and his co-founders decided against pursuing stem cells and soft tissue R&D because for any startup, it will be challenging to raise the required "deep funding". He adds that the next step up for Supercraft3D is to finalise a joint research project with NUS and NTU for the development of a standard knee implant design customised for the Asian anatomy. The grant for this project is expected to be approved this October or November.
Advances in medical technologies will surely help push the boundary doctors now face in saving lives but Shelley's Frankenstein is unlikely to transcend from fiction to reality anytime soon.