The shape of things to come

In October 2017, history was made at the All India Institute of Medical Sciences (AIIMS) Delhi. Doctors at the country’s premier medical college and hospital separated a pair of 28-month-old craniopagus (joined at the head) twins, Jaganath and Balram, from Odisha, after a two-stage, 48-hour marathon surgery. Deepak Kumar Gupta, paediatric neurosurgeon who led the team along with well-known neurosurgeon AK Mahapatra, is clinical in his summing up. He says, “So far, only six cases of conjoined twins have been reported in India. This is the first time we could save both the children.”

The procedure once again put the spotlight on additive manufacturing, popularly known as 3D printing. Ahead of the surgery, Gupta developed a 3D-printed model of the twins’ skull, complete with its entire vessel and brain architecture. “By practising on 3D-printed models, risks are minimised for a patient. We can do such complex operations in India now, and no longer have to send children abroad for neurosurgical operations,” says Gupta, who conducted mock trials with several skull types, including those made by Osteo3D, a Bengaluru-based start-up.

Gupta has been simulating with 3D-printed skulls for the past four years, especially before he operates on children with malformed heads. “With these models, you can precisely understand which parts have to be operated upon, and where to create incisions,” he says.

3D-printed models are not useful for simulations alone. Earlier in 2017, Medanta Bone and Joint Institute’s chairman and chief surgeon Sanjiv Kumar Singh Marya and senior surgeon V Anand Naik implanted a 3D-printed titanium vertebra in a school teacher who was suffering from tuberculosis of the spine. This was the world’s second such operation and the first of its kind in India. The 32-year-old’s condition was an outcome of an infertility treatment she was undergoing. The steroids in her injection had weakened her immune system, causing tuberculosis to damage her second and third cervical bones. “The first option was to treat using traction and give her medication, allowing her to heal over a period of time. The second was to make her upright and improve her mobility,” reveals Naik. Since the patient was in extreme pain, the first option was ruled out.

For this case, Medanta approached Sanjay Pathak of Global Healthcare, a Delhi-based company, which initially created a prototype of a three-centimetre-long 3D-printed vertebra from ABS (Acrylonitrile butadiene styrene) plastic, a common thermoplastic polymer, followed by the final titanium implant. The pores in the titanium implant were designed to let blood flow, and the hollow was filled with bone graft. “The micro-porous body (of the titanium implant) allows the bone cells to go inside the implant, and eventually grow through and over it,” mentions Pathak, who is also the co-founder of Alignwise, a company that makes dentistry implants.

“Typically, in the case of cadaveric bone implants (using bone from a third person) the cell regeneration process takes a minimum of two to three years. On the other hand, a 3D-printed part is usually made of materials such as titanium or coated with hydroxyapatite (the salt which a bone is constituted of) and so there is no weakening at any stage. The healing is faster,” elaborates Marya. It’s been two years since the operation and the teacher has since resumed her job. 

In 2018, AIIMS replaced an entire hip with a 3D printed titanium model. Earlier, the patient had opted for a traditional implant but it failed, destroying a larger part of the bone. The medical fraternity seems to be gradually warming up to 3D implants, but it has certainly taken a liking to 3D-printed models for surgical preparation.

Role model

In 2015, Swati Garekar, a paediatric cardiologist at Fortis Hospital in Mumbai, faced a challenging case of a nine-month-old diagnosed with a congenital heart condition. The child had both the arteries emerging out of the right ventricle instead of one each from the right and the left. As a result, its pure (or oxygenated) blood was mixing with the impure stream. Garekar tried an echocardiogram and a CT scan, but neither gave a clear picture. She then turned to 3D printing since she had heard about heart models being used in complex cases abroad. 

She tried to get leads from her contacts overseas but nothing turned up. Finally, it was pure serendipity. Garekar randomly called up 3D-printing firms operating out of the city and was put through to Firoza Kothari, co-founder and CTO of Mumbai-based Anatomiz3D. “Firoza was keen on working on the project, with little discussion on commercials,” says Garekar. A sandstone 3D model was made. 

“Since we could afford only an opaque model, we sliced the prototype to help the surgeon understand what he could expect when he would cut open the right ventricle, aorta, and the septum,” says Garekar. It was India’s first 3D printing-aided cardiac surgery for an infant. The same year, two other cardiac surgeries were done using similar models.

Over the past five years, more hospitals have turned to 3D-printed models for complex surgeries. “Echocardiogram is a beautiful tool that helps in 90% of the cases, but for the 10% complicated cases, it’s always nice to have a plan before you walk into the operation theatre,” says Garekar, who has used these models in 15 such cases.

There is a growing incidence of thickening of the aorta (the artery that carries blood from the heart to the body) among Indians, thanks to longer lifespans. To cure an aortic aneurysm, doctors generally graft a stent inside a blood vessel, to reinforce the artery’s wall. Thus far, they have been going in with little idea about the size of the stent that would be needed. Ajay Kaul, chairman and HOD, cardiothoracic and vascular surgery at BLK Super Specialty Hospital, says, “With the aid of 3D-printed models, we can get the exact measurement of the stent and put it inside the aorta.” Usually, doctors try two to three stents if the first one doesn’t work. “In a complex surgery, time is of essence; you can’t keep operating for hours. That’s where 3D printed models can help,” elaborates Kaul, adding that every year 2-3% of these procedures involve 3D-printed hearts at BLK Hospital in Delhi.

The trigger

Incidentally, 3D printing is not a new technology; it has existed since the 1980s. In fact, IIT-Bombay and IIT-Kanpur, besides the Nashik-based Datar Switchgear (later merged with L&T), brought India’s first such printers in 1997.

Bhallamudi Ravi, chair professor (mechanical engineering) at IIT-Bombay, first saw the innovation in 1989 at an exhibition in Germany. Nearly a decade later, after receiving a grant, IIT-B purchased a polymer-based 3D printer from Stratasys in 1997. “We managed to negotiate the price down to Rs.3 million from Rs.10 million,” says Ravi. And the first 3D-printed model in India was made in 2001 by IIT-Bombay — a mould for a patient who did not have ears. The doctors then used the ceramic mould to create a silicone gel ear. Similarly, Tata Memorial Hospital, in 2003, approached the institute to create prosthesis for a 50-year-old patient from Karnataka who was suffering from bone cancer. Ravi says, “Earlier, each 3D-printed model would cost at least Rs.50,000-80,000, but it has now fallen to one-tenth of what MRI imaging costs.” Thus far, the institute has built over 100 such prototypes, including of hearts.

But the acceleration in adoption of 3D printing was triggered by the expiry of patents, intense competition and innovation. When the patent for the most primitive form of 3D printing, known as fused deposition modeling (in which the 3D print is created by laying layers of a material) expired in 2009, and selective laser sintering (in which the model is created by fusing powdered material under heat) patent expired in February 2014, it resulted in an explosion of open-source desktop printers selling for $300. According to reports, the global 3D-printer market in healthcare is expected to grow to around $4 billion by 2022, led by nearly 150 industrial 3D-printer manufacturers. By 2023, Gartner predicts that 25% of medical devices in developed markets will use the technology for pre-surgical planning and to replace joints, surgical implants and prosthetics.

Anand Prakasam, country manager (India), EOS, a global leader in 3D printers with 19% market share, believes that 3D printing has become much more than a prototyping technology. “We have seen massive improvement in mechanical properties, hardware and materials. The prints are more accurate and better in quality. This can be transformational for the medical industry, considering the high level of customisation required to meet patient needs,” explains Prakasam.

In fact, the rapid advancement in 3D printing has spawned a whole host of start-ups (See: Growth stage). A former GE Healthcare executive, Deepak Raj Karunakara, was among the first to set up a 3D-focused start-up, Osteo3D, in India in 2014. Since then, about nine start-ups have emerged, either bootstrapped or in incubation centres. “Five years ago, I had to spend a lot of time in convincing the doctor. Now we discuss the kind of materials being used. The understanding has evolved,” says Karunakara.

Osteo3D has a proprietary cloud-based platform that enables doctors to upload CT scans and MRI records of patients. Thus far, the start-up has supplied over 1,300 models to 100 hospitals, largely across Bengaluru, Chennai, Mangaluru and Pune. Kothari of Anatomiz3D, says, “In 2015, when we founded the company, there were hardly any enquiries. Today, we are working with close to 150 doctors.” Similarly, Pathak of Global Healthcare mentions that his company has built over 100 prototypes, besides implants. “Implants are not an everyday business. The Indian market will take about five years before 3D-printed implants become mainstream,” he feels. Meanwhile, start-ups are scaling up in bioprinting.

More than skin deep

Following a ban on using animals for testing cosmetic products by the EU in 2013, the quest for an alternative led to the invention of bioprinting. This is an additive manufacturing process that uses biomaterials (a biological or synthetic substance) that imitate human tissues.

Building on the bio-printing initiative, at the Consumer Electronics Show in the US this year, Johnson & Johnson showcased Neutrogena MaskID, a 3D-printed face mask made from 3D images of a customer’s face. Using a selfie from a smartphone 3D camera, the Neutrogena Skin 360 system determines the placement of ingredients for a dermatological treatment based on the person’s face. The algorithms in the software divide the selfie into six zones: forehead, eye area, nose, cheeks, chin and nasolabial folds. The data collected, thus, is used to create a personalised mask.

The ban on animal testing has prompted pharma and cosmetic companies to look for alternatives for skin testing. Closer home, in 2014, FMCG major ITC approached professor Sourabh Ghosh from the Department of Textile Technology at IIT-Delhi to develop bioprinted skin constructs using human cells. “For this specific project, not only did ITC provide funding support, but also collaborated scientifically,” he mentions.

Finally, in early 2018, Ghosh and his two-member research team created a 3D scar tissue model through tissue engineering. “Cosmetic screening is done on either animal skin or skin from dead bodies. But animal models do not accurately represent the structure of human skin. There is also large donor-to-donor variation if those skins are collected from humans. But bioprinted skin models ensure uniformity and reproducibility, as well as flexibility to create any dimension as needed,” explains Ghosh.

The bioprinted skin, which has been patented, is already being used by ITC. The researchers will now explore the possibility of growing hair on this skin. The team has developed a 3D hair follicle structure in collaboration with ITC. Eventually, the institute is looking at launching a start-up to develop different diseased skin conditions to test drug molecules.

A Bengaluru-based start-up, Next Big Innovation Labs, is already close to a commercial launch of its 3D skin tissue. Co-founder, Pooja Venkatesh, says, “We have used our proprietary technology to create a bioprinted skin tissue called Innoskin and Innoskin FT. Our long term goal is to develop a clinical version of Innoskin which can be used to heal burns and skin injuries.” Globally, the commercially available reconstructed human epidermis models are EpiSkin, SkinEthic and EpiDerm, which cater to a $500-million market comprising cosmetic, pharma, and CRO (contract research organisation) players.

The start-up has received over Rs.10 million in grant from the Karnataka government, the Centre and Tata Trusts, and is being incubated at the Bangalore Bioinnovation Centre. It is among the only two Indian companies to have made it to Merck’s accelerator programme. “We have partnered with the world’s oldest pharmaceutical and materials company (Merck) to develop novel 3D bioprinting solutions, and have also partnered with a leading FMCG major in India for our Innoskin line of products,” reveals Venkatesh. In a first, the start-up is also looking to patent its bio-ink, formulated entirely in-house. “We are also patenting our customisable bioprinter called Trivima,” adds Venkatesh. 

In another breakthrough, IIT-Delhi has also developed a 3D-printed cartilage using bio-ink, comprising bone marrow-derived cartilage stem cells, and silk proteins in high concentration. The bio-ink supports growth and survival of cells and the silk protein ensures the cartilage’s similarity to its natural counterpart. Ghosh reveals that the institute has initiated a study into the intersection of bio-printing with developmental biology, with IIT-Kanpur and a few European research laboratories. “This knowledge would be very useful to revert features of osteoarthritis. A major European pharma company is also in the loop, which has greatly increased translation potential of our research to industrial level,” reveals Ghosh.

Organ(ic) growth

The next big frontier for researchers is bioprinting of organs, known as organoids. Research labs across the world are working on bioprinting ‘organoids’. These are derived from stem cells aimed at replicating the complexity of an organ. They have a lifetime of a couple of months, thus allowing repeated testing, which comes in handy in the drug discovery process. Currently, researchers have created organoids resembling brain, heart, lung, kidney, retina, intestine and liver.

In the US, Organovo, which designs and develops functional human tissue for medical research and therapeutic applications, is working on creating a fully functioning human liver. It conducted a successful transplant of its 3D bioprinted human liver tissue patches on to the livers of mice. Similarly, China-based Sichuan Revotek has transplanted a part of a printed human artery into a simian. Organovo believes it will be able to cure chronic liver failure by enabling the discovery and safety assessment of new drugs in the near future.

At Tel Aviv University, researchers have 3D printed a heart using a patient’s own cells and biological materials. It contains cells, blood vessels and chambers unlike the earlier 3D printed heart structures. Though the model is currently small — the size of a rabbit’s heart — the researchers have revealed that a human heart does require the same technology and are confident of creating a near human heart. In late 2018, CollPlant, an Israeli 3D bioprinting company, and United Therapeutics Corporation, the US-based biotech company, got the licence to develop and commercialise 3D bioprinted lung transplants. The agreement combines CollPlant’s proprietary collagen derived from genetically engineered tobacco plants, and its bio-ink technology, with the regenerative medicine and organ manufacturing capabilities of United Therapeutics subsidiary, Lung Biotechnology.

The University of California, San Diego, has upped the game by many levels — by figuring out a way to create functioning ‘miniature brains’. According to Nature magazine, the ‘mini brains’ began producing brainwaves spontaneously, and the electrical patterns were similar to those in premature babies. However, the organoid is not exactly similar to a human brain, as it does not contain all the cell types found in the cortex (responsible for processing sensory information) and is also not connected to other brain regions. While the researchers hope to ‘network’ the brain with other organoids and create a complex structure, Kaul of BLK Hospital, rules out 3D printing accomplishing this. “If you ask me whether brains can be replicated, it’s next to impossible. Grey matter (neurons) can’t be created,” says Kaul.

Closer home, Bengaluru-based Pandorum Technologies, supported by the department of biotech under the BIRAC programme, has created a lab-grown mini liver and a bioengineered ‘liquid cornea’ for human implantation. While liver implants will take a while owing to regulatory approvals, Pandorum is working with LV Prasad Eye Hospital for bioengineering corneal tissues and its implantation. If you have an injured cornea, Pandorum’s liquid cornea — a suspension of cells with a biopolymer — would be applied to the wounded area. Then it goes inside and solidifies. Tuhin Bhowmick, co-founder and director at Pandorum Technologies, says, “The product is ready for animal studies, and should be ready in a few years. If all goes well, it would probably be the first tissue-engineered product in the country to be implanted inside a patient.” 

Though artificially-made organs are yet to make their way into human bodies, for a country such as India, every little progress matters. According to estimates, 500,000 people die each year, owing to organ failure. As per the National Organ and Tissue Transplant Organisation, only 8,000 kidneys are transplanted against the need for 200,000 annually. Similarly, only 3,000 livers and 100 hearts are available against the need for 50,000 livers and 30,000 hearts every year. The shortage is despite a study by the Sanjay Gandhi Postgraduate Institute of Medical Sciences stating that the country’s entire organ donation shortage can be met even if 5% to 10% of victims involved in fatal accidents serve as organ donors. But lack of awareness (both among doctors and families), religious beliefs, and police intervention are seen as the biggest deterrents.

While the wait for 3D-printed organs in India would likely be a long one, additive-made implants are sure to see a lot more adoption in the coming years.

Growth pangs

As with most sectors, right pricing will be key to adoption of 3D-printed implants. At present, in India, very few can afford regular implants. According to Hospaccx Healthcare Business Consultancy, the orthopaedic implants market is divided into four segments: trauma, spine, knee and hip. Over the years, the government has slashed the prices of knee implants by 60-70%. The price of the widely used cobalt chromium in knee replacement surgery, as per Hospaccx, costs Rs.54,720 against its earlier price of Rs.158,324 a year ago. Similarly, the price of special metals required to make the implants has been slashed by 70% from Rs.250,000. For a replacement knee implant, prices have been reduced by 60%. The National Pharmaceutical Pricing Authority (NPPA), the country’s independent regulator for drug pricing and ensuring availability of medicines at affordable prices, noted that, annually, 20 million patients need arthroplasty, a surgical reconstruction or replacement of a joint, but only 100,000 could afford it. In 2018, a Public Interest Litigation was filed in the Delhi High Court against overpricing of medical devices, with a specific plea for intraocular lenses (implanted in the eye to treat cataracts or myopia), to be listed as a drug by the NPPA.

Do 3D print implants then run the risk of coming under price controls? The question arises, especially since 3D printed titanium prosthetics offer huge advantage over conventional implants. Ravi of IIT-Bombay explains, “When you put a conventional metal implant, the adjoining bone starts weakening in the absence of load as the implant takes on the entire load.” In fact, in cases where metal implants fail, 3D printed implants are the solution. Pathak adds that since metal implants are available in pre-defined sizes, there are chances of rejection as well.

Pathak points out since 3D printed implants are customised, the cost will be always 5-10x higher than regular implants. In the case of a hip replacement in 2018, Global Healthcare made the implant for Rs.500,000. “It would have cost nearly Rs.3.5 million if it was imported, that’s nearly 7x the cost. The ones made in India are built with wafer-thin margin,” he explains. Prakasam of EOS India believes implants are expensive because the machines are not extremely fast, and raw materials are not cheap either. Today, a cranial implant would cost around Rs.200,000. “You can get one made for Rs.50,000 as well. But the question is: how much is a patient willing to pay for the value addition? Unless people understand the value, it’s going to take time,” says Prakasam.

Osteo3D’s Karunakara also believes that 3D printing adoption would take time, as it is a complex and slow process. “An inkjet printer can churn out 35 pages a minute, but a 3D printer can’t churn out skull models or implants at that rate. It’s a slow process that also involves post-processing,” says Gupta.

The other big impediment is that almost 80% of Indians are not covered by any health insurance, which makes it difficult for patients to even incur the additional burden of a basic 3D printed model. According to an EY report, health insurance penetration rate is only 20% in the country. Garekar of Fortis says, “Since the first case in 2015, I have only handled 15 cases involving 3D printed models. The number could have been 5x higher if patients were able to afford it.” A key reason is that structural heart defects by birth are not covered under insurance. “An average family struggles to pay even Rs.200,000 for an open-heart surgery and they have no insurance cover.   They have to rely on savings or some state-based scheme. Hence, even a Rs.15,000-20,000 3D printed model is a huge burden for such patients,” points out Garekar. She adds that, in some cases, she relies on 3D software models to bring down the cost.

But things could change in the future, if 3D printed models and implants are considered a part of the standard operating procedure by the healthcare sector. Ravi of IIT-B reveals that the institute is working on creating a standard operating procedure (SOP), involving 3D printing. IIT-Bombay has the only biomedical engineering and technology (incubation) center or BETiC lab in the country to have ISO 13485 certification of quality management system for medical devices. Chander Shekhar, additional director general of Indian Council of Medical Research, the apex body for formulation and promotion of biomedical research, says, “We don’t have an independent opinion [on 3D printing] and would be keen to see what experts from IIT-Bombay have to say. Let us see how the consensus is emerging, and then we will definitely take it up [SOP that includes 3D printing].”

Even as the framework for 3D printing in healthcare is taking shape, the big positive is that an ecosystem involving start-ups, institutes, and hospitals is already working effectively. For now, institutes such as the IITs and CSIO, an arm of the CSIR, have installed high-end titanium implants. Players such as Global Healthcare are getting their implants made from these institutes. But it’s unlikely that hospitals are going to end up investing in 3D printers that make implants. “Hospitals by design are service oriented and lack a manufacturing DNA. It’s not about selling a printer to the market, we need a large player to set up the ecosystem. Revisions need to be done to ensure consistency in quality,” feels Prakasam. EOS India is in preliminary talks with two or three large business houses to help create a large ecosystem around 3D printing in healthcare. “They will probably opt for a franchise model with small labs across the country,” reveals Prakasam.

While the future looks promising, Marya believes a lot depends on how patients warm up to the concept. “In cases such as these, patients ask for a definitive promise of success. Somehow, in healthcare we are expected to be foolproof in our country, more so when a lot of money is at stake. While 3D printing will make life easier for patients, for sure, it cannot make gods out of doctors.”