3D Printing in Medicine – Implications for Insurance

Urs Widmer, Ramiro Dip, 18 Apr 2016

In 2012, a medical team at the University of Michigan in Ann Arbor had a difficult problem with a baby who had been born with the rare condition tracheobronchomalacia, where one portion of his airway was so weak that it persistently collapsed. Breathing was difficult, even on a ventilator. How could the area of weak tissue be repaired? By a dangerous operation?

The ideal tool for this delicate task was a 3-D printer. 3-D printing (3DP, also known as additive manufacturing) was developed in the 1980s by the American engineer Charles Hull. Carmakers can design complicated parts on a computer and print prototypes. Three-dimensional printers are now inexpensive. Today’s printers print in plastics, but also in metals, ceramics, wax, and even food. The medical procedure at the University of Michigan in the child with tracheobronchomalacia profited from experience with 3DP at the Michigan College of Engineering and the automotive industry, which is eager to transform production.  CT scan data of the baby’s chest was converted into a three-dimensional virtual map of the narrowed airways. This map led to the design and printing of a splint—a small tube made of biocompatible material—that would fit over the weakened airway and hold it open. It would expand as the baby grew. The splint was biodegradable and would last for three years, long enough for the cells to grow over it. Approval for use through FDA's emergency-use authorization program had been obtained. Three weeks after the splint was implanted, the baby was home. In a 2013 issue of The New England Journal of Medicine, the Michigan team reported that the baby was thriving without any "unforeseen problems related to the splint"1. A wider medical community took notice of this medical 3DP innovation. In the meantime, additional two children have benefitted from 3DP splints for similar airways problems at the University of Michigan.

Spectrum of 3D printing in medicine - From education to regeneration

After Charles Hull pioneered 3D printing, few medical examples surfaced for over a decade. Over the last couple of years, however, interest in applications for medicine has been increasing. Actual and potential medical uses for 3D printing can be classified into broad categories:  1) creation of anatomical models, customised prosthetics and implants 2) pharmaceutical printing affecting drug dosage and delivery and 3) tissue and organ printing.  Benefits of the new additive manufacturing in medicine include customisation and personalisation of medical products, drugs, and equipment. 3DP could be cost-effective and lead to increased productivity. The individual production steps could be split among several parties with effectively enhanced collaboration. 3DP technology is already up and running in many medical areas, as can be seen from a random list of 3D-printes examples:

  • iLab/Haiti prints umbilical cord clamps for local hospitals

  • Printed models of complex congenital heart disease prepare doctors and safe surgery time 

  • Cheap and easily customisable prosthetics such as hands or limbs for Uganda

  •  Tailor-made printed titanium parts replace insured or missing skull portions

  • 3DP of intervertebral discs or human ear cartilages including built-in electronics

  • Biocompatible, biodegradable devices deliver chemotherapy to treat bone cancer

  • 3D skin printing directly onto the wounds of burn victims

  • Dual-syringe 3DP of alginate, smooth muscle cells and interstitial cells produces heart valves that are tested in animals

  • 3DP binds chemicals to ceramic powder for scaffolds that promote regenerative bone growth 

  • Bio printing blood vessels using temperature-dependent dissolving ink

Expectations of the new 3DP technology are often exaggerated in the media, and the public has unrealistic expectations about how soon some of the exciting possibilities will become a reality. However, what has already been achieved seems spectacular. Many 3DP medical products are only adaptations of existing products. More transformative applications for 3DP technology will need more than a decade to evolve, and significant scientific challenges currently remain. The costs to bringing 3D printed medical devices to clinical use are high, and regulatory hurdles are considerable. But if successful, 3D bioprinting could challenge traditional paradigms of medical device manufacturing and health care. Last but not least, crowdsourced 3D printed prosthetics for disabled children in both the developing and Western world is an impressive example for how 3DP processes can lead to the democratisation of design, manufacturing and distribution. We can conclude that 3D bioprinting has already been used for the generation and transplantation of various different tissue - including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. 3D printed tissues with cells are mainly sheet-like structures with cells being laid down within a scaffold structure.

Future bioprinting of tissue and organs - Major roadblocks and potential solutions

Even advanced additive manufacturing is limited by the palette of standard polymers and metal alloys. A wider assortment of novel materials, from living cells to semiconductors, is under development. The precise combination and localisation of “inks” could lead to spectacular results2. Bioprinting can be seen as precise spatial patterning of living cells and biologics. Computer-aided deposition, layer-by-layer, could produce living tissue and organ analogs for regenerative medicine or biological studies. By arranging multiple cell types, 3DP can recapitulate tissue biology, and bioprinting is seen as a game-changer in the development of tissue constructs.3 However, the printing of blood vessels is not resolved. Every viable tissue needs a network of vasculature. The materials scientist Jennifer Lewis and her team at Harvard University have succeeded with a promising experiment4. Crucial to Lewis’s success is what she calls fugitive ink, which liquefies when cooled, leaving behind a hollow canal that can be filled with cells. 3-D-printed cellular tissues will eventually serve as the building blocks of whole organs.

There has been significant interest in whether 3D organ printing is possible, and the general consensus is that we are a number of years away from this. Indeed, it may not be possible to replicate the complicated structure of a 3D organ, but it may be possible to develop a structure that simulates or amplifies the activities of that organ. The key conference for 3D printing is "Inside 3D Printing Conference and Expo", which started in 2013, and is currently on a world tour with events in New York, Seoul and Tokyo. This conference covers a number of different vertical streams, including medicine, technology, automotive and software. Key organisations include Organovo (developing tissues to test toxicity), Oxford Performance Materials (developing bone implants for facial reconstruction and replacing bones in feet and hands), e-NABEL (producing prosthetics), University of Michigan Ann Arbor (producing tracheal splint), Forest Baptist Medical Centre (early stage development of functional kidneys that may instead constitute layers of kidney cells), and Harvard University (printing of blood vessels through use of fugitive ink). CellLink unveiled the first universal bioink, which is aimed at 3D printing living and fully functional 3D tissue models. 3D bioprinters typically have two separate extruders, one for laying down a "bio-ink" and another for laying down cells onto that ink. CellLink mixes the cells and bioink and allows a single nozzle on the bioprinter to lay down both bioink and cells at the same time. This allows for greater detail and precision as well as the ability to speed up the printing process.

Regulation - FDA approval of 3D printed medical applications

In October 2014, the FDA held a workshop on 3D printing for medical device makers entitled "Additive Manufacturing of Medical Devices: An Interactive Discussion on the Technical Considerations of 3D Printing". This was interpreted as an encouragement to develop and register 3D printed products for medical applications. 3D Printing is an opportunity for innovation in the health care industry. However medical devices and drugs are tightly regulated. Hurdles to get clearance are high, development and registration costs are high, and innovation must occur within the current FDA regulatory framework for medical devices. Experience with the differences between traditional medical devices and additive manufactured products are limited. The FDA’s Additive Manufacturing Working Group is operational, but little specific guidance has been released. 3DP can be viewed as a component of precision medicine (formerly personalised medicine), complementing genomic medicine and the use of stem cells. The case of a tracheal splint by 3D printing at the University of Michigan to treat critically ill newborns illustrates the potential contribution of additive manufacturing for precision medicine. Medical device manufacturers might be hesitant to move forward with 3DP in view of regulatory uncertainty and high costs for getting FDA approval. However, the FDA does not seem to be as perplexed by additive manufacturing as it was feared. After all, 3D printing is just a manufacturing technology, an enabling technology, not something completely unusual that has not been seen before. Questions arise such as 1) Who is the manufacturer? 2) Where does manufacturing occur when 3DP is used? 3) How are products cleaned? 4) How were processing agents removed from the final product? And 5) How is biocompatibility guaranteed?

Table 1. FDA approved 3D printed Medical Products – A sample of 6 examples from a list of 85 approved Medical products. Legend: OPM: Oxford Performance Materials, Inc.

FDA Approval

Product

Manufacturer

2013

3D printed polymeric cranial device implant

OPM

2013

Cranial bone void filler

Tissue Regeneration Systems

2013

Triathlon titanium tibial baseplate, used for total knee arthroplasty

Stryker Corporation

2014

3D printed polymeric implant for facial indications

OPM

2014

3D printed denture base

DENTCA

2015

Spritam™ (levetiracetam), 3D-printed prescription pill for therapy of partial onset seizures in patients with epilepsy

Aprecia


The FDA has already approved 85 3D printed medical devices. Most of them were handled via the 510(k) or emergency use pathways. Typical examples include spinal cages, dental devices, and hearing aids with 3-D printed components. Most approved devices are personalised, but not completely novel. Truly novel 3-D printed medical devices probably will get premarket approval (PMA). Holding back with novel 3-D printed medical devices might reflect the attitude of many companies to wait for someone else to test the regulatory waters. In 2015, the FDA approved an epilepsy medicine called Spritam that is made by 3D printers. It could be the first in a line of 3DP central nervous system drugs. The pill’s unique structure allows it to dissolve considerably faster than the average pill, which is appreciated by seizure sufferers who were prescribed large, hard-to-swallow pills. 3D printing guarantees that the medicine will be delivered in the exact dose intended, as each pill will be completely uniform. While the quick-dissolving Spritam tablet is a world away from 3D-printed organs and body parts, its approval shows that the FDA thinks certain 3D-printed materials are safe for human consumption.

Implications for Insurance

In 2014, biomedical 3DP applications represented approximately 14 percent of the USD 4.1 billion revenues generated by companies providing 3DP printing equipment, materials and services5. With the prospect of an ever increasing number of applications and the improvement of existing technology and processes, 3DP industry revenues are expected to reach USD 21 billion by 2020, with a 10-20 percent contribution from the biomedical sector5. This fast-evolving highly-technological industry creates novel landscapes that require novel insurance considerations.

3D printed products, such as a hand prosthesis or hip implants, are personalised, but are otherwise not significantly different from what we are used to insuring. However, the various steps of commercial 3D printing add complexity to issues such as intellectual property, data protection and product liability. Taking safety and labeling as an example, 3DP products are subject to the same regulations as conventional products, but the current global and regional regulatory environments are not prepared for the ambiguity of a 3D printing process. The prevailing concept is that 3D printed medical devices are to be manufactured at approved, fit for purpose facilities; in this context, 3D printing is not any different from manufacturing such devices in a well-controlled good manufacturing practice (GMP) environment. This is how they have been so far regulated by the FDA. However, as technology enables new applications, it is conceivable that 3D manufacturing will have to take place closer to the patient, which would complicate the chain of parties involved in the process, and lead to potentially overlapping liability responsibilities and the associated regulatory challenges. Similarly, in the case of 3D printed pharmaceuticals, who will be held liable in the case of adverse reactions? Additional risks related to 3D printed products include the acquisition and transfer of personal data, as well as the liability of designer and software engineers. For example, online platforms allow sharing computer aided design (CAD) files that users can edit and print. How will the customisation and product quality control be tracked? How will data privacy be secured? In this context, changes in product liability laws may be needed to secure adequate consumer protection.

Other important questions relate to the printing materials themselves and the actual printing process. The use of novel polymers, sometimes mixed with nanoparticles, poses long term risks for implants and needs post marketing surveillance and registries. Long term risks of 3DP products depend on body location, duration and function. Could the printable ingredients or printer itself be regulated as medical devices? Similarly, a variety of questions arise in relation to new and evolving 3D printing processes, such as fused deposition modeling, selective laser sintering, stereo lithography, and 3D plotting/Direct-Write/bioprinting. As 3D printing blurs boundaries between the steps in traditional manufacturing and commercialisation chains, new business models will arise to accommodate these needs, which will require innovative insurance approaches.

The impact of 3DP on the economy, and on medicine in particular, is likely to become significant within the coming years, and we can expect 3D-printed biomedical elements to become increasingly more commonplace. One could potentially imagine the delivery of a customised sterile prosthesis and instruments for joint replacement to the operating room. Also, bio-printing promises to offer great precision medical solutions through the exact placement of cells, proteins, drugs and even genes to guide tissue generation. Another exciting development is 4D printing, that is, 3D printed objects that can adjust their shape or properties to stimuli from the environment. However, current technical limitations and the high costs associated with the development of 3D printed medical devices allows progress only in incremental steps. However, insurers should take this opportunity to gather experience in the field that can help them anticipate risks as 3D printed medical devices move into more tightly regulated, but equally relevant areas. While this technology has the potential to disrupt the current health care landscape, it will certainly create challenges and opportunities for the insurance industry.

References
1. Zopf DA, Hollister SJ, Nelson ME, Ohye RG, Green GE. Bioresorbable airway splint created with a three-dimensional printer. N Engl J Med. 2013 May 23; 368(21): 2043-5.
2. Ledford H. The printed organs coming to a body near you. Nature. 2015 Apr 16; 520(7547):273.
3. Ozbolat IT. Bioprinting scale-up tissue and organ constructs for transplantation. Trends Biotechnol. 2015 Jul; 33(7): 395-400.
4. Compton BG, Lewis JA. 3D-printing of lightweight cellular composites. Adv Mater. 2014 Sep 10; 26(34): 5930-5.
5. Wohlers report 2015. 3D Printing And Additive Manufacturing State Of The Industry. Annual Worldwide Progress Report. ISBN 978-0-9913332-1-9.

 

See also the event "Expert Forum on 3-D printing", which took place at the Centre for Global Dialogue in September 2015.

See also the summary of the event.

Authors

Urs Widmer

Senior Medical Officer, Swiss Re

Urs Widmer graduated from Zurich University Medical School in 1979. After postgraduate research work in a metabolic unit and a specialty degree in internal medicine (1988) he did research at the Rockefeller University, New York on the cloning of novel chemokines. After 13 years as an attending physician in internal medicine and consultant for clinical immunology at Zurich University Hospital he joined Swiss Re in 2005 as Senior Medical Officer.

Ramiro Dip

Senior Risk Engineer, Swiss Re

Ramiro Dip is a Senior Risk Engineer in the Casualty Centre at Swiss Re. He graduated from Rosario University Veterinary School, Argentina, in 1997. Following some years in private practice, he obtained a doctoral degree in toxicology and a PhD in molecular biology from the Universities of Bern and Zurich in 2005. He then established and led an independent research group with interest in molecular and translational aspects of inflammation signaling at the University of Zurich. Between 2011 and 2015, he held different R&D roles at Novartis, and in 2015, he joined Swiss Re. Ramiro is also a regular lecturer in pharmacology at the University of Zurich, and a guest lecturer in molecular toxicology at the University of Basel.

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