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Making precise structures at the smallest scale

Attractive tools for biomedical and pharmaceutical research Imagine a tiny sensor setting off an alarm when a healing wound gets infected, or the effects of an experimental drug being tested not on a human or animal, but using a tiny chip packed with biological cells and sensors. The biomedical field is more and more turning to technology at the smallest scales. Dr. Luigi Sasso, at the Department of Precision and Microsystems Engineering (PME) works to enable the large-scale fabrication of such small-scale technologies. The latest addition to the set of tools at his disposal is an advanced 3D printer (called the Nanoscribe) that routinely produces structures as small as 20 millionth of a millimeter. “We’re very happy that we can now cover the full resolution range,” Sasso says. Organ-on-chip An exciting avenue being pursued in the area of personalized medicine is to test treatment options for each individual patient using only a small amount of cells or tissue. How do you channel nutrients or drugs towards these cells and achieve a real-time read out of how they respond to these drugs? Sasso uses soft plastics, called polymers, to build tiny structures incorporating, on the one hand, channels for the transport of liquids and, on the other hand, sensors. “Polymers are biocompatible: cells like them better than other materials. They can also be made to conduct electricity, which allows them to be crafted into electrochemical sensors.” These sensors are sensitive to biomedical parameters such as the local acidity (pH), temperature or glucose levels. As Sasso explains, “The blood’s glucose level, for example, provides information about a cell’s metabolism, while changes in the pH of a wound that’s in the process of healing can indicate an infection taking place.” When such sensors are embedded in structures designed to hold cells and channel liquids, miniature laboratories are obtained (an approach called ‘organ-on-chip’) that are very attractive tools for biomedical and pharmaceutical research. Replicating With the basic concepts proven in laboratory conditions, for Sasso and his team, the challenge lies in ways to precisely and reliably replicate the systems, paving the way for large-scale production and use. Their main technique to replicate polymer-based structures is that of soft embossing. In this approach, a mold is created and used to ‘stamp’ the desired structures into soft polymer material. The length scales of these structures vary from the micro (1 micrometer = 1 thousandth of a millimeter) to the nanoscale (1 nanometer = 1 millionth of a millimeter). “The smaller and more precisely the structure can be made and, most importantly, replicated, the better,” explains Sasso. Drug development Take, for example, research on drugs that help prevent kidney stones. Kidney stones are due to substances found in urine that initially form crystals and eventually macroscopic stones. . In order to speed up drug testing, biomedical researchers are looking for tiny test substrates that can host the basic material making up these crystals, and that allow the drug under study to be introduced and its effect on the crystal growth monitored. It has been found that the growth of the kidney stone crystals on polymer substrates can be controlled by carefully designing the surface structure: the more the surface mimics the crystal structure of the kidney stone material, the faster the material grows and the quicker it can be used to evaluate new drugs. Sasso’s approach to mass-produce finely structured polymer substrates can therefore help speed up drug development. 3D printing on the nanoscale Attaining the highest resolution is key to Sasso’s work, which is why his latest tool, nicknamed the ‘Nanoscribe’ after the company that supplied it, is such a big deal. “We now have access to all relevant length scales, from 20 nanometer to the millimeter scale.” To print 3D structures on these small scales, the Nanoscribe uses a technique inspired by conventional chip fabrication. During the chip fabrication step called lithography, a thin polymer layer is partly illuminated with UV light. The illumination affects the local chemical structure of the layer, so that, in a next step, the non-illuminated areas can be dissolved and removed, leaving only the parts that were originally illuminated. Instead of UV light, the Nanoscribe uses a 2-photon absorption process to illuminate the polymer layer, one 3D pixel of 20 nm in size at a time. “We are very excited to welcome the Nanoscribe. It opens new avenues for our group. Well before it arrived, my students were already planning one project after another.” The smallest Rietveld chair in the world The Nanoscribe will undergo a series of tests to verify its ability to produce nanoscale features as small as 20 nanometer. As a first exercise in operating the machine, Sasso programmed it to 3D-print a Rietveld chair of 100 micrometer (one tenth of a millimeter) in size. “Although huge in terms of what the Nanoscribe can do, we thought it was fun to start simple. The result is beautiful.” The new machine could reproduce the entire Madurodam miniature park in just a few square centimeters. Diversity In the development chain stretching from idea to product, Sasso focuses on enabling technologies, developing the methods and techniques that will be vital to fabricating future products on a larger scale, most notably tools for biomedical research. In other words, he brings exploratory laboratory concepts to users worldwide. Sasso comments: “Delft is a very fruitful place for this type of research. There is a very good collaborative spirit in the Department of Precision and Microsystems Engineering. Our researchers cover all relevant disciplines, from theoretical modeling to experimental approaches. This diversity allows us to look at challenges from different angles. Our engineering mentality makes us an attractive partner to complement biomedical experts.” Next frontier In his quest to find solutions to reproducibly structure materials and to increase the functionality of these structures, Sasso’s next frontier is that of composite materials, where non-polymeric materials, such as nanoparticles, are added to the mix, introducing new functionalities to the system but also new challenges to the production and replication process. “These are challenges we’re ready to take on,” concludes Sasso. NERI The department PME initiated the NanoEngineering research Initiative (NERI). NERI is a platform for long-term collaboration of industry and academia to jointly turn nanoscience into industrially relevant applications: Moving nano from lab to app. Moving nano from lab to app requires a new knowledge and technology foundation that allows the development and engineering of repeatable and reliable relevant functions and applications at an industrially relevant scale. This challenge requires cooperative efforts from both industry and academia. Luigi Sasso

Photonics for faster Internet

A major challenge in photonics is the accurate alignment of photonic chips, lenses and mirrors that are used in miniscule devices. Researcher Marcel Tichem works on a method to let this part of the assembly take place inside the device itself, known as on-chip assembly. That would make production more accurate and much faster than current manual production processes. A promising application for this novel assembly concept are devices for the transfer of data over fibre optic cables. Marcel Tichem is an Associate Professor at TU Delft’s department of Precision and Microsystems Engineering (PME). His work is set in the world of high-tech systems, where precision, speed and reliability are of the essence. “Companies like ASM International, NXP, ASML, and FEI create complex, high-performance machines and instruments. We develop new concepts for the control and actuation of precision systems and microsystems, and for automated design”, says Tichem. “Such concepts make it possible to meet the high demands of optical systems: the precision alignment of lenses and mirrors, for example.” Fibre optic data transfer One application of Tichem’s work is fibre optic data transfer. The bandwidth of traditional copper-based cable and the amount of data that can be sent are limited, but the demand for data traffic keeps growing. In fact, the explosive growth of online video and mobile data threaten to grind the internet to a halt. Then there is the sustainability factor. “Copper is not very energy-efficient”, he says. “That is why you find these colossal datacentres next to even more colossal cooling systems, often in a port area so enough water for cooling is available.” Using fibre optics could solve both problems. “You can transfer so much more data over fibre optic cable, and it doesn’t produce excess heat.” Chip design: TJ Peters, Photo: Hans de Lijser “Photonic chips work with light instead of electrical signals. They can detect or generate light waves, change their colour and so on”, explains Tichem. “Such micro-sized structures are very difficult to produce. Imagine, for example, that you have to make a tiny laser source that emits a stable beam and can continue to do so over a lifespan of a few decades.” After years of research, however, The Netherlands are now at the forefront of photonic chip development, and Photonic Integrated Circuits (PICs, the optic version of traditional microchips) can be produced at a reasonable price. But photonics are an order of magnitude more complex than electronics. Photonic devices, called packages, contain micro‐optics and electrical components, as well as PICs. On-chip MEMS for photonic alignment “Such a package is really a complex photonic system. Particularly the integration and alignment of all the parts make the assembly extremely complex, and industry does not have the technology yet to automate this process”, Tichem says. He is working on that though: his current research focusses on microscopic mechanical devices, or MEMS for on-chip photonic alignment. “We are integrating tiny mechanicals systems on the chips, so they can help align their photonic elements.” This research is part of an STW project as well as an EU-funded project PHASTFlex (Photonic Hybrid Assembly Through Flexible Waveguides) that is looking into automated assembly systems in response to the needs of the data communications sector. Within this project, cooperation exists with major European players working on applications and photonic chips (LioniX, Oclaro) and precision assembly (ficonTEC, Aifotec). Photo: TJ Peters” Micromachines 2016 , 7(11), 200; doi: 10.3390/mi7110200 A first achievement on the road towards full automation would be the automatic alignment of two PICs in one package. “In electronics assembly, machines can pick and place thousands of chips per hour. In optical assembly, this is still operator based, using microscopes and precision stages”, says Tichem. Project PHASTFlex is working on a two-step process. First, a machine picks up the PICs and places them on one substrate, with an accuracy of a few micrometres. The machines can do this, but this is still far too inaccurate for perfect alignment. That is the task of the on-chip MEMS. “On one of the chips we integrate an assembly machine consisting of tiny motors, or actuators. With the help of these actuators, you can slightly adjust the position of flexible waveguide beams on one chip in relation to the other.” As the name suggests, the assembly functionality is added solely for the purpose of assembly. “You only use it once. That takes space on your systems, and it costs money, but you have to offset that against current production methods that are labour-intensive.” PME The department of Precision and Microsystems Engineering (PME) is one of TU Delft’s departments working on technologies that can be used in optics. PME’s specific mission is to use the phenomena and technologies of the small-scale to create breatrhough innovations of smart materials, systems and devices. “We are mostly involved with mechatronics, meaning systems that have to move very accurately”, says Tichem. “Optics are only one field of application. Smart materials give new possibilities for improved performance of systems. Tichem explains: “The alignment of mirrors and lenses is critical in optics. However, alignment can change under the influence of temperature fluctuations, for example. You can try and minimise the effects of that by designing a structure, parts of which will not expand under the influence of heat.” That is called topology optimisation, a field that is also important for modern additive manufacturing technology. Optic technologies – or photonics, the term we use in relation to optical microsystems – are on the rise. Hence, a future chair of the department will focus solely on micro-optics and micromechatronics for photonics. Already the department is developing important enabling technologies. “A lot of what we do here can help others improve optic systems, whether these are medical instruments, inspection cameras or measuring instruments.” The department PME initiated the NanoEngineering research Initiative (NERI). NERI is a platform for long-term collaboration of industry and academia to jointly turn nanoscience into industrially relevant applications: Moving nano from lab to app . Moving nano from lab to app requires a new knowledge and technology foundation that allows the development and engineering of repeatable and reliable relevant functions and applications at an industrially relevant scale. This challenge requires cooperative efforts from both industry and academia. PME also takes part in the recently initiated Dutch Optics Center (DOC). Marcel Tichem

A diet for steel

Smaller mix of elements, easier to recycle If it were up to Erik Offerman, steel would go on a diet. He believes that half of the alloying elements in steel are superfluous. A diet would be more sustainable, better for the environment and make it easier to recycle steel. Even better, it wouldn’t reduce the quality of this popular construction material, according to Offerman. The materials scientist from Delft is basing his audacious assertion on his expertise of the microscopic structure of steel – which is what determines its properties, he says. ‘Steel producers add all kinds of elements to achieve the right properties. Chromium, vanadium, nickel, niobium, molybdenum, to name a few: every type of steel has its own cocktail of elements. Our research shows that with precise process control you can also achieve those properties – or better ones – by adjusting the microstructure. And you don’t need all those additional elements. More with less.’ Offerman is a keen advocate of resource-efficient production: don’t use what you don’t need. ‘Being efficient with elements’ is inherently sustainable, but in the case of steel there’s another important benefit. Recycling is considerably simplified when fewer alloying elements are used. Many elements ‘get in each other’s way’ and can only be separated with a great deal of energy. ‘We now know that recycling often results in steel products of lower quality,’ Offerman says, ‘in which elements accumulate. The fewer elements there are in steel, the smaller that problem will be and the easier it will become to control quality. Then a real cycle will be within reach, in which no value is lost.’ Designing resource efficiency: know how to grow The growing global economy requires an increasing amount of raw materials, and that means a greater burden on the environment. Newspapers tend to focus on CO 2 emissions because of the climate problem, but the impact that metal mines are having on local environments cannot be underestimated either. The United Nations has already come to that conclusion: sustainable development requires disengaging economic growth and the pressure that this puts on the environment and the planet’s reserves. It’s as clear as day to Erik Offerman too: we have to start moving towards a resource-efficient, circular economy. ‘That’s an enormous challenge to which I would like to contribute,’ he says. Offerman argues that the discussion about the availability of elements is mistakenly focusing on high-tech products such as smartphones. ‘A number of these elements are found in steel as well. If you look at the percentage though, then it doesn’t amount to much: sometimes it involves tenths of a per cent in steel. But steel is produced in massive quantities, more than a billion tons a year. So we’re talking about considerable amounts of alloying elements too.’ Eye opener The fact that Offerman’s research on materials focuses on sustainability considerations is special. ‘Like many materials scientists I have worked on a scale of a micrometre without taking the larger picture into account. In 2013, for example, we published a piece about a grade of steel that was much more fire resistant. This kind of steel probably would have prevented the Twin Towers in New York from collapsing, or at least kept them standing a little longer despite being on fire. That would have given people more time to escape. But we would have needed to use the element niobium to make that steel. It’s mined in Brazil; that country controls more than 90% of the market. That’s a geopolitical risk that steel producers prefer to avoid. So our discovery, which was a nice breakthrough technically speaking, turned out to have little use practically .’ This ‘eye-opener’ made Offerman realise that researchers shouldn’t only specialise but also develop more horizontally. ‘You have to be aware of the challenges and changes in society. I’m trying to convey that to my students in our teaching as well now.’ It should be noted that the development of heat-resistant steel was not in vain. ‘We’re now trying to see whether we can give steel similar properties by using vanadium. It has a similar effect as niobium, but it’s a much more widely available element.’ Complex steel production Offerman explains that it’s important when making steel to get the right mix of different kinds of microcrystals (ferrite, martensite and austenite, says the expert). They differ from each other in terms of atomic structure, and the added alloying elements largely determine which crystals will appear. But, and this is the crux of the matter according to Offerman, the way that the steel is treated during production also has a major impact. And it’s precisely because modern steel manufacturers are so skilled at that complex production process that all these alloying elements aren’t really necessary in practice. In recent years, Offerman has developed different computer models that shed light on this, and this is what prompted him to come up with the notion of a steel diet. ‘The models provide a well-founded indication of what is possible. But of course we need to experiment now. First to improve our models, and ultimately to show that you really can produce good steel with fewer elements.’ He is convinced that this will find support from the industry. ‘A resource-efficient cycle of materials ultimately means reducing costs. Manufacturers won’t need to buy as many expensive elements and can recycle at less cost. If we can demonstrate what’s possible, then people will certainly show an interest in it.’ Steel production is a complex process. It starts with molten pig iron, to which other elements are added ('alloying'). That mixture is poured, cooled and rolled into rods, sheets and rolls of steel. In any case, that’s the simple explanation. In practice, manufacturers use sophisticated mechanical and heat treatments, in which the steel is heated and then cooled again, slowly or quickly, often multiple times, always at different temperatures. The manufacturer also knows, when rolling the steel, sometimes hot, sometimes cold, exactly which setting leads to which kind of steel. Even the machines belonging to customers of steel manufacturers, such as the presses used in the car industry, contribute to the final properties of the end product (the body of a car, for example). Offerman is regularly in contact with Tata Steel IJmuiden and also works with NedSchroef from Helmond, an international producer of screws, bolts, nuts and other fasteners, for the car industry, among others. Research director Emmy Öhlund from NedSchroef shares Offerman's view that there is a future for alloys with fewer elements. Together they examined a new, extremely strong grade of steel from Japan, which turned out be unexpectedly good at resisting high temperatures. They were able to come up with an explanation by systematically studying the relationship between the alloying elements used, the microstructure and the properties. It won them the Sawamura Award last year from the influential Japanese iron and steel institute ISIJ. Even more important was the fact that the research revealed that only three per cent of alloying elements actually yielded adequate properties, and at high temperatures – even though the types of steel available for that are often ‘chock full’ of alloying elements. The amounts are as high as fifteen to even forty per cent sometimes. ‘The properties of these super alloys are sometimes much more than what we need, but we use them because steel manufacturers have nothing else to offer us in their product range,’ Öhlund says. She knows that cheaper grades of steel with fewer alloys present opportunities, but has to add that a great deal of patience is needed to reach the point where new materials are actually used. ‘For demanding buyers, such as the car industry, a new material is only suitable once it has gone through all kinds of tests and been certified. That can take a long time. We recently started selling a new fastener, for example, which we initially presented in 2009.’ A new materials system According to Offerman, Dutch and Belgian steel researchers are at the forefront when it comes to developing new sustainable grades of steel. ‘I don’t know exactly what’s going on inside industrial laboratories, but I know of relatively few scientists in academic research that share our viewpoint. I think that we, as materials scientists and as TU Delft, could really achieve something. It would be great if we could succeed in reinventing the materials system and redesign it so that we can create a closed cycle that uses relatively little energy and doesn’t cause environmental problems.’ Erik Offerman conducts his research as part of the Leiden Erasmus Delft Centre for Sustainability, an inter-university partnership in the area of sustainability. He manages projects in the area of resource efficiency and material cycles. With his colleagues at Delft, he focuses primarily on production-technical aspects, while Leiden takes the environmental aspects into account and Erasmus University the business side of things. Offerman also participates in the Raw Materials project of the European Institute of Innovation and Technology (EIT), which is one of the largest initiatives worldwide to promote the more sustainable use of resources. He is one of the few steel researchers in the consortium, which has more than a hundred partners from twenty European countries.

Autonomous boats

TU Delft - Professor Rudy Negenborn tells you more about Autonomous vessels In 2030 the captain will be sitting somewhere onshore instead of on his ship. From his sophisticated wheelhouse, which will look like the inside of an air traffic control tower, he will survey all ships that want to enter the port of Rotterdam. By moving his fingers across the touchscreen in front of him, he will access detailed information about each vessel, about its course and speed, for example. The captain will be barely involved in the logistics of it all anymore, because in the future ships will synchronise their schedule with container terminals, locks and bridges. He won’t need to stand at the helm anymore either, nor will there be any need for sailors on board. Instead, vessels will establish contact themselves with their commander when, for example, it’s very busy on the water and they have ended up in a precarious situation. Or if a part breaks down. That’s when the captain will take over again. As a result, he will be able to navigate multiple ships simultaneously. Advantages autonomous boats The major advantage of unmanned boats is that it reduces the cost of transporting cargo by forty per cent. ‘As a result, cargo will be transported more often by ship than by car,’ says Rudy Negenborn, researcher of automatic control for transport engineering and logistics at TU Delft’s ME Faculty. That right there is one of the most important social benefits of autonomous boats. Moreover, it dovetails with the European objective of making cargo transport more sustainable: by taking it off the roads and onto water and railway tracks. To give an example of more sustainable logistics: in ports, containers could be moved more often by autonomous ships instead of autonomous transport vehicles. ‘If you can lower the cost of transport by water even more, then it really is a more attractive option.’ The costs can be reduced in another way as well: because ships, container terminals, bridges, locks and other parties in the port automatically exchange information with each other, they can agree on how fast ships will move to a given destination and which form of navigation they will use to pick up and deliver their cargo. This kind of centralised coordination is still lacking right now. ‘All inland vessels let the terminals know what time they’re going to arrive. But if the crane on the quay isn’t working up to speed, then delays are inevitable,’ says Negenborn. The rise of increasingly large cargo ships means that soon there will be higher peaks in the number of containers that are being delivered, which will cause greater queues in ports. High time, in other words, for better coordination, which will make the entire port area more efficient and ensure that goods are delivered according to schedule more often. It’s one of the most important research areas at the Delft University of Technology. Autonomous boats are also safer, according to the scientists at Delft. ‘Currently, 75 to 95 per cent of all accidents at sea are partly caused by human error,’ says Robert Hekkenberg, researcher of maritime technology. He shows a picture of an accident in the English Channel, one of the busiest shipping routes in the world, in which two ships collided with each other. ‘It happened because the crew wasn’t paying enough attention. After one of the ships sank, three more banged against them. We can prevent this kind of human error in the future by automating things, including navigation.’ Design But how realistic is this future, if you consider that the law in 150 countries prescribes that there always be a crew on board? Hekkenberg believes that the legal framework will have been adapted by 2030. Completely redesigning ships is at least as much of a challenge, because they were originally conceived to be operated by a crew. ‘If there are people on board, they can walk through the complex machine installation, put their hands against it, listen to what is happening, replace a filter and make minor repairs. If there are no longer any humans on board, then today’s ships will break down in no time.’ And that’s a major problem if you’re in the middle of the sea and there’s no port in sight. Hekkenberg’s most important research challenge therefore is how to completely revamp the ship and its engine room. ‘Much of what we base our ship designs on comes from regulations that aim to protect people’s lives, and moreover we have great confidence in human beings to perform all kinds of tasks, varying from maintenance and navigation to throwing out a rope, answering the radio and fending off pirates. A ship without a crew would be a very different animal, because things like the wheelhouse and the lifeboats will be superfluous. In short, we haven’t had to give such fundamental thought to ships since we moved from wooden sailing vessels to steel steamships. The notion of autonomous boats is completely altering our design framework. We’re essentially witnessing a major system change.’ The Delft University of Technology is at the forefront in that respect, together with the Scandinavians. TU Delft is the frontrunner in the Netherlands and works closely with the entire shipbuilding world, including the research institutes Marin and TNO, shipping companies, pilots, people who guide ships in the port, companies that establish technical demands on ships, major shipbuilders, equipment suppliers, ministries and industry associations. In order to study how ships can communicate with the greater transport process, the Delft University of Technology is working primarily with logistical planners such as operators of container terminals, ports and inland vessels. Nonetheless, autonomous boats are not only an engineering challenge for the Delft scientists, as there are also legal and financial obstacles that need to be overcome. ‘To enable a ship to look around itself, you can use standard radar equipment. It will see a great deal, but far from everything. You can also use military radar, which costs ten times as much but sees everything,’ Negenborn says ‘How are we going to derive benefits from autonomous boats and simultaneously develop a good business case?’ But hold on, what’s going to happen with all of those sailors once they’re stuck onshore? Are they all going to be fired? ‘Lower-skilled workers will probably gradually lose their jobs, but at the same time the number of jobs in the maritime sector has doubled in recent years. This number will continue to rise because global trading is rising, and that means that the number of ships needed will increase as well. Since these ships are becoming increasingly autonomous, new positions will be created in production, Hekkenberg says. That means that not only the captain but also the sailor will be setting foot onshore in 2030. In the media ‘Developing the roboat’ TU Delta, 14-12-2016 Autonomous shipping as a possible solution to impending labour shortages in the shipping sector Phys.org Technology, 13-12-2016 Other articles in Dutch click here Robert Hekkenberg “In short, we haven’t had to give such fundamental thought to ships since we moved from wooden sailing vessels to steel steamships. The notion of autonomous boats is completely altering our design framework. We’re essentially witnessing a major system change” Rudy Negenborn "The major advantage of unmanned boats is that it reduces the cost of transporting cargo by forty per cent. ‘As a result, cargo will be transported more often by ship than by car.' "

Research Benno Hendriks

It’s important during cancer operations that the tumour is completely removed. In order to do this as accurately as possible, surgeons base their operation plan on images that were made during the diagnostic phase with imaging techniques. Surgeons then have to largely rely on their senses during the operation. According to Benno Hendriks, part-time professor of optics for minimally invasive instruments at TU Delft and research fellow at Philips Research in Eindhoven, we can do better. All too often, a piece of affected tissue is left behind or healthy tissue is damaged by the operation. This can lead to repeat surgery, extra treatments and worse patient outcomes. More feedback during the operation could change that. How? According to Hendriks by adding optical feedback in surgical instruments. Put simply, it involves recognising tissue with the aid of light. Different molecules absorb and emit light at different wavelengths. We see that as colour, which is why blood is red, for example, and fatty tissue yellow. ‘With spectroscopy we look at these colours of the light. It enables us to distinguish more accurately than we can with our eyes,’ says Hendriks. Biopsy needles made from optical fibre technology He applied that principle in recent years by providing biopsy needles with optical feedback. ‘When you take a tissue sample from a lung, for example, it inevitably moves during the procedure as a result of breathing,’ Hendriks explains. ‘So no matter how precise your X-ray or MRI images are, there’s always the risk of imprecision during the placement of the needle.’ To solve that dilemma, Hendriks and his colleagues equipped biopsy needles with optical fibre technology. ‘The ends of the optical fibre are placed in the tip of the needle. One optical fibre functions as a light source, which it shines into the tissue; another optical fibre collects the light that went through the tissue and that signal is transmitted to a detector,’ he explains. This makes it possible to read the tissue and determine whether it’s normal or abnormal tissue. Of course, it has to first be clear how to distinguish between normal and abnormal tissue. A great deal of research went into that. ‘I measured all kinds of tissues in different situations in hospitals,’ Hendriks says. ‘To begin with at the pathology department with tissues taken from patients.’ He worked together with the Netherlands Cancer Institute for this, for example. Armed with knowledge about the tissue, he subsequently began to incorporate the technology into the biopsy needles. ‘That’s quite complex, because it’s a moving system. The last step in the development process is to then validate your instrument in practice.’ Introduction into the market Once all these steps in the development process have been taken it’s up to the business unit – of Philips or another company – to assess whether it’s the right time to introduce the innovation into the market. Money plays a role of course. Hendriks also conducted research on the possibilities of using a similar system for nerve tissue recognition during local anaesthesia, for example. ‘During local anaesthesia you have to place the needle very close to the nerve. If you’re too far away from it, it won’t work. If you do it in the wrong place, you can damage the nerve,’ he says. Spectroscopic imaging of the nerve tissue would help. ‘But anaesthesia needles are quite inexpensive tools. There is always a limit to what the technology is allowed to cost. If an anaesthesia needle or a biopsy needle becomes too expensive as a result of the innovation, then it won’t be used after all.’ Smart surgical knife Though it may seem as if new technology equates additional costs, in reality it can save a great deal in medical and social costs. Another of Hendriks’ ideas is to adapt the popular electric surgical knife, which is used to cauterise tissue. ‘You could make a knife like that smart, so that the tip of the knife recognises the tissue before you start cutting,’ he explains. ‘So it only cuts when you press on the button, and that can easily be integrated into the feedback loop. If it gives you a signal telling you to stop, then the knife stops immediately.’ However, you cannot take the spectroscopic tissue recognition that’s used in biopsy needles, for example, and use it in exactly the same way in a surgical knife. ‘This is much more complex, because when you cut, you also alter the tissue a bit in the vicinity of the knife. It’s similar to meat that turns brown when you fry it. In other words, it affects the optical signals that you’re receiving.’ ‘We therefore have to first conduct all kinds of research on the interaction of the knife with the tissue,’ he continues. Back to square one, in other words, and to the pathology lab. And that’s just the beginning, because how do you then integrate the feedback into the knife with precision and simultaneously retain the other functions? Surgeons have to be involved in this research too. ‘How exactly do you use the knife? When is it useful for a surgeon to receive feedback? And then there are many other questions that will need answering in the coming years,’ Hendriks says. The surgical knife is only one example. ‘Many other instruments are used during operations, such as sutures and devices to make connections between intestines. You could make all of these smarter and thus prevent all kinds of complications.’ Innovation & cooperation Integration and cooperation are indispensable factors in this. ‘The magic word for innovation in the medical world is “simple”. It has to be easy to use and intuitive,’ Hendriks says. ‘That’s also the approach at Philips: if you take your innovations to a hospital, make sure that they aren’t a bunch of loose components but a total concept.’ According to Hendriks it’s the concerted effort of all parties that determines an innovation’s success. ‘Part of the solution lies with companies such as Philips, part with TU Delft and another part with the hospital. So you have to start working together early in the process.’ He believes a good example is the coronary catheterisation lab, where diagnoses are made but also where stents are used to treat narrow arteries and heart valves are even replaced through the groin. ‘Something that used to require an open heart operation can now be done with an intervention that takes a couple of minutes. Once you’re done on the table, you can go home, so to speak,’ says Hendriks. ‘That’s the power of the integration of systems such as imaging, navigation and instruments. As a result, something highly complex has been made simple.’ Personal motivation With his new chair, many of the components that need to be integrated in the operating room are coming together. ‘TU Delft, for example, is strong in building steerable instruments, such as those used in keyhole surgery. Here we are also looking at the workflow in operating rooms and how to train physicians to use new systems.’ Hendriks sees great opportunities ahead. ‘In most operations today, it all comes down to the skill of the surgeon. If you can manage to take image guidance from the diagnostic stage to the operating room, then you’ve already taken a big step forward. And if you can combine that with sensing technology and feedback, you’ll advance the entire field. That’s my goal.’ ‘As a research fellow at Philips I have the opportunity to explore new directions and delve into my subject more extensively,’ Hendriks says. ‘Research at a company does have a different focus: a company opts for things that have potential today. A university has the liberty to look at things in the long term.’ He sees his dual role as an opportunity to bring the two closer together. ‘You can’t do it on your own. As a company, you can’t test all of the new directions that will become interesting in a few years. On the other hand, it’s of little use for a university to invest in potential solutions just to discover years later that no one wants to use it in practice. I want to help to bridge these two situations.’ Benno Hendriks

3D-printing and origami

Image reproduced by permission of Shahram Janbaz from Materials Horizons, 2016 DOI: 10.1039/C6MH00195E The latest bone prosthetics are 3D-printed. They are custom made and have pores which are invaded by bone cells. Yet, materials scientist Amir Zadpoor believes the implants can become even more effective - by using origami of biomaterials. The surgeon steps back for a moment. Gently a scanner spins over and around the patient on the operating table. Equipment in the corner awakens and spits out a peculiar flat sheet with gaps and strips. It falls into a jar filled with liquid and starts to swell and fold. After a few minutes, it perfectly fits the cavity the surgeon just had to make to remove a large bone tumour. The prosthetic is quickly clicked in place. This is how Amir Zadpoor, materials scientist at Delft University of Technology, envisions the future of 3D-printed implants. “The prosthetics will consist of a layered, porous material that easily adheres to natural bone”, he predicts. “The pores will be quickly occupied by new, healthy bone. Within months the implant will be almost indistinguishable from real bone, and will last a lifetime.” It’s a long way off, acknowledges Zadpoor. But also a logic next step in what is happening in the clinic today. Custom made 3D-printed prosthetics are already rescuing patients own bone. Sander Dijkstra, orthopaedic surgeon at Leiden University Medical Center: “Just a few days ago, one of my patients told me that he had been jogging again. That’s wonderful and very rewarding.” Before the introduction of 3D-printed implants Dijkstra always had to remove the total knee joint of people with a large malignant tumour in the femur. “Especially for young people it is a terrible prospect to never be able to run again.” Porous The 3D-printed prosthetics that Dijkstra currently uses are partially porous. That is the result of research by materials scientists such as Zadpoor: “We helped developing 3D-printing techniques for porous, yet strong implants. Because of the porosity, the surface of these implants is many times larger, which means that the antibacterial surface coating is many times more effective. Moreover, bone cells can settle down in the pores. That provides a better integration with the body and strengthens the implant.” All a very welcome improvements, finds Dijkstra. Currently, one in every seven implants needs to be replaced. “Implants may loosen and wear out. Young patients in particular run the risk of having a prosthetic replaced later in their life.” Additively manufactured (3D printed) porous biomaterials aimed for bone tissue regeneration manufactured at the Additive Manufacturing Laboratory, TU Delft (Medical Delta © de Beeldredacteur). When 3D-printed prosthetics last longer, why isn’t every implant printed? Zadpoor: “At the moment, these implants are still relatively expensive because their manufacturing involves many specialists. I expect costs to decline substantially over the coming years. After that, standard implants could indeed also be printed.” Still, Zadpoor doesn’t expect to see 3D-printed hip replacements on the market any time soon. “Those kinds of implants are extremely optimized products causing very few complications. To replace them, benefits need to be large and proved conclusively. That requires long-term research.” Schoulder blade At the moment Dijkstra places a 3D-printed prosthetic about once every four months. It is certainly no standard procedure. The orthopaedist is one of the pioneers. The 3D-printer doesn’t stand in the surgery yet, but at a specialized company called Implantcast (Germany). Dijkstra: “We make a CT-scan of the affected bone and decide which part needs to be removed. Using specialized software, we design a prosthesis that will perfectly fit on the remaining bone above the knee. The top is attached to a standard pin which is anchored to the healthy upper part of the femur.” The whole procedure from design to surgery takes about seven weeks. Doctors and engineers deliberate at several stages on the optimal design of the implant. In the meantime, the patient receives chemo therapy to treat possible metastases. The group of patients that qualify for a 3D-prosthetic is small: young people with severe bone tumours. And the technique is only used when standard implants provide no satisfactory solution. Dijkstra has also replaced half a shoulder blade and part of a pelvis – bones for which no standard prosthetics exist. Dijkstra: “A new product always comes with a risk. An unknown, unexpected weakness may present itself over time. As a physician, I’m well aware of that. We first treat patients that will gain the most by a 3D-printed implant and follow them closely over a longer period in time.” Also a copy is manufactured of every 3D-printed implant Dijkstra places. Scientists at the Delft laboratories examine if it could be improved further. Origami Zadpoor wants to fuse 3D-printed prosthetics even further with the body. To achieve that, the material scientist wants the ‘impossible’. For about ten years, it’s evident that a particular surface pattern on implants can stimulate the growth of bone cells. Probably, the cells like to attach to this particular surface because it resembles natural bone well. Zadpoor wants to incorporate this pattern in the pores of 3D-printed implants. However, it’s a nanopattern: ridges with a height of only a few thousands of a millimetre. Zadpoor: “Such a nanotopography can be created with techniques from the semiconductor industry, but only on flat surfaces. The technique is not compatible with 3D-printing.” Zadpoor wants to resolve this problem with ‘self-folding materials’. “Think of origami”, Zadpoor starts his explanation. “You start with a flat piece of paper, but end up with a highly complex folded form.” The idea is to print flat structures and apply the desired nanopattern onto them. Then a folding trick applied. The printed material is made from various layers of passive and active polymers. These materials shrink or swell when the temperature rises, when they become moist or when light is falling upon them. Zadpoor: “We combine the metamaterials in such a way that flat objects spontaneously fold themselves or roll up.” Self-folding origami Millions The European Union granted Zadpoors idea in 2015 with 1.5 million euro (ERC-grant). Recently, the first visible results were delivered: a staircase-like shape that turns into a DNA-like structure under water and a cellular structure that transforms into a patterned shape. But how do these origami materials result in the porous 3D-printed implants with nanotopograhy that will help patients? Zadpoor: “This is fundamental research. We have now provided proof-of-principle in how 2D-materials can fold themselves into 3D-structures. It will take a lot of further experiments to finally create the durable implants we want.” Self-twisting of DNA-inspired constructs To reach that final goal, Zadpoor cooperates with several hospitals in and outside the region and with large and small businesses. He also participates in large, international research projects such as the recently started PRosPERoS ( PRinting PERsonalized orthopaedic implantS ) with a budget of nearly five million euros. Zadpoor's laboratory in Delft has become an important hub in the development of new biomaterials. Yet, he could easily have worked at SpaceX or Boeing. Zadpoor holds a PhD-degree in Aerospace Engineering. “Six years ago, I made a well-considered decision to switch from aircraft materials to biomaterials. After all, nothing is more rewarding than to help curing people.” Read the press release here . Nederlandse media Door origami geïnspireerd botherstel Nemo Kennislink, 25 oktober 2016 Origami en 3D-printen voor zelfbouwende materialen De Ingenieur, 22 oktober 2016 TU Delft gebruikt origami voor 3d-objecten met oppervlaktepatroon Bits & Chips, 24 oktober 2016 TU Delft combineert 3D-printen met orgimami-technieken voor implantaten ICT & Health, 1 november 2016 3D-printen en origami bij ontwikkeling zelfvouwende medische implantaten (video) Engineersonline.nl, 23 oktober 2016 Zelfvouwend origami-botweefsel uit de 3D-printer BNR radio, 24 oktober 2016 Zelfvouwende medische implantaten door 3D-printen en origami Nano House, 30 oktober 2016 Kennis van Nu, 2 maart 2017: International media 3-D printing and origami techniques combined in development of self-folding medical implants Phys.org, 21 oktober 2016 TU Delft researchers pioneer self-folding medical implants using 3D printing and origami techniques 3ders.org, 24 oktober 2016 3D Printing and Origami Could Yield Self-Folding Medical Implants Engineering.com, 24 oktober 2016 Self folding medical implants 3dprint.com 3D PRINTING & ORIGAMI TECHNIQUES FOR MEDICAL IMPLANTS 3dprintersonlinestore.com, 2-11-2016 3d-printing and origami techniques combined development self folding medical implants ECNmag.com http://it.sohu.com/20161029/n471739916.shtml http://md.tech-ex.com/engineering/2016/47549.html Bio Focus: Nanopatterned self-folding origami may open up new possibilities in tissue engineering MRS Bulletin, 28 november 2016 Bio Focus: Nanopatterned self-folding origami may open up new possibilities in tissue engineering MRS Bulletin, 7 november 2016 Shape Memory Polymers to Create Origami-like Biomplants EdgyLabs, 8 november 2016 3D printanje i origami tehnike u kombinaciji razvoja samosklopivih medicinskih implantata Skala.ba, 6 november 2016 TU Delft researchers develop self-twisting of DNA-inspired constructs (VIDEO) 4dpmmconference.com, 26 oktober 2016 Amir Zadpoor