NEWS POST: Harvard Scientists Use 3D Printer To Create 4D Flower

© Harvard University

The latest creation from scientists at Harvard marks a new chapter in biology-inspired engineering. Two teams of scientists worked together to advance 3D microscale printing capabilities with a product that is responsive to time.

Scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University, and the Harvard John A. Paulson School of Engineering and Applied Sciences, have taken their 3D printing technology up a level – to the fourth dimension.

Their biology-inspired creation attempts to mimic natural structures that are able to change form in response to their environment. The Harvard scientists unveiled a “hydrogel composite structure” that resembles an orchid and can change shape when submerged in water.

“This work represents an elegant advance in programmable materials assembly, made possible by a multidisciplinary approach,” senior author of the study Jennifer Lewis said. “We have now gone beyond integrating form and function to create transformable architectures.”

The 4D-printed orchids are programmed with precise and localized swelling, and contain cellulose fibrils, or tiny fibers, from wood. They are meant to function in place of the microstructures that enable plants to change shapes. The outcome is that the make-up of the orchid responds to water – the stimuli – much the same as a typical plant organ such as tendrils, leaves, or flowers might.

As the first layer of the liquid-like hydrogel is laid by the printer, it quickly hardens as the cellulose fibrils are aligned and the composite ink is encoded with directionally-dependent stiffness and swelling. They are then formed into a pattern that results in the orchid’s ability to take intricate shapes. Not only is the orchid then able to move in varied directions, but it can be predicted and controlled.

As the scientists point out in the Harvard Gazette, “The new method opens up new potential applications for 4D printing technology, including smart textiles, soft electronics, biomedical devices, and tissue engineering.”

The results of this innovation are dependent on the materials used, and can be tuned to be more conductive of electricity or for more biocompatability. “We can control the curvature both discretely and continuously using our entirely tunable and programmable method,” said Elisabetta Matsumoto, a co-lead author.

This series of images shows the transformation of a 4D-printed hydrogel composite structure after its submersion in water. Credit: Wyss Institute at Harvard University

Materials science and mathematics combine to enable the printing of shapeshifting architectures that mimic the natural movements of plants

A team of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Harvard John A. Paulson School of Engineering and Applied Sciences has evolved their microscale 3D printing technology to the fourth dimension, time. Inspired by natural structures like plants, which respond and change their form over time according to environmental stimuli, the team has unveiled 4D-printed hydrogel composite structures that change shape upon immersion in water.

"This work represents an elegant advance in programmable materials assembly, made possible by a multidisciplinary approach," said Jennifer Lewis, Sc.D., senior author on the new study. "We have now gone beyond integrating form and function to create transformable architectures."

Lewis is a Core Faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Hansjörg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Science (SEAS). L. Mahadevan, Ph.D., a Wyss Core Faculty member as well as the Lola England de Valpine Professor of Applied Mathematics, Professor of Organismic and Evolutionary Biology, and Professor of Physics at Harvard University and Harvard SEAS, is a co-author on the study. Their team also includes co-author, Ralph Nuzzo, Ph.D., the G.L. Clark Professor of Chemistry at the University of Illinois at Urbana-Champaign.

In nature, flowers and plants have tissue compositions and microstructures that result in dynamic morphologies that change according to their environments. Mimicking the variety of shape changes undergone by plant organs such as tendrils, leaves, and flowers in response to environmental stimuli like humidity and/or temperature, the 4D-printed hydrogel composites developed by Lewis and her team are programmed to contain precise, localized swelling behaviors. Importantly, the hydrogel composites contain cellulose fibrils that are derived from wood and are similar to the microstructures that enable shape changes in plants.

Reported on January 25 in a new study in Nature Materials, the 4D printing advance combined materials science and mathematics through the involvement of the study’s co-lead authors A. Sydney Gladman, who is a graduate research assistant advised by Lewis and specializing in the printing of polymers and composites at the Wyss Institute and SEAS, and Elisabetta Matsumoto, Ph.D., who is a postdoctoral fellow at the Wyss and SEAS advised by Mahadevan and specializing in condensed matter and material physics.

By aligning cellulose fibrils during printing, the hydrogel composite ink is encoded with anisotropic swelling and stiffness, which can be patterned to produce intricate shape changes. The anisotropic nature of the cellulose fibrils gives rise to varied directional properties that can be predicted and controlled. This is the reason that wood can be split easier along the grain rather than across it. Likewise, when immersed in water, the hydrogel-cellulose fibril ink undergoes differential swelling behavior along and orthogonal to the printing path. Combined with a proprietary mathematical model developed by the team that predicts how a 4D object must be printed to achieve prescribed transformable shapes, the new method opens up many new and exciting potential applications for 4D printing technology including smart textiles, soft electronics, biomedical devices, and tissue engineering.

"Using one composite ink printed in a single step, we can achieve shape-changing hydrogel geometries containing more complexity than any other technique, and we can do so simply by modifying the print path," said Gladman. "What’s more, we can interchange different materials to tune for properties such as conductivity or biocompatibility."

The composite ink that the team uses flows like liquid through the printhead, yet rapidly solidifies once printed. A variety of hydrogel materials can be used interchangeably resulting in different stimuli-responsive behaviors, while the cellulose fibrils can be replaced with other anisotropic fillers of choice, including conductive fillers.

"Our mathematical model prescribes the printing pathways required to achieve the desired shape-transforming response," said Matsumoto. "We can control the curvature both discretely and continuously using our entirely tunable and programmable method."

Specifically, the mathematical modeling solves the "inverse problem", which is the challenge of being able to predict what the printing toolpath must be in order to encode swelling behaviors toward achieving a specific desired target shape.

"It is wonderful to be able to design and realize, in an engineered structure, some of nature’s solutions," said Mahadevan, who has studied phenomena such as how botanical tendrils coil, how flowers bloom, and how pine cones open and close. "By solving the inverse problem, we are now able to reverse-engineer the problem and determine how to vary local inhomogeneity, i.e. the spacing between the printed ink filaments, and the anisotropy, i.e. the direction of these filaments, to control the spatiotemporal response of these shapeshifting sheets."

"What’s remarkable about this 4D printing advance made by Jennifer and her team is that it enables the design of almost any arbitrary, transformable shape from a wide range of available materials with different properties and potential applications, truly establishing a new platform for printing self-assembling, dynamic microscale structures that could be applied to a broad range of industrial and medical applications," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital and Professor of Bioengineering at Harvard SEAS.
This work was supported by funding from the Army Research Office (ARO) and the National Science Foundation’s Materials Research Science and Engineering Centre (MRSEC).

Originally published in RT (STORY 1) and Wyss Institute website (STORY 2)

GUEST BLOG POST: We Need To Innovate The Innovation Process — Greg Satell

Synopsis

We need to shift from a disjointed effort that puts researchers on one side of a great divide and industry on another, to a combined, interdisciplinary effort.

By Greg Satell

All too often, we see innovation as a single event. A genius like Steve Jobs envisions a thousand songs in our pocket and the iPod is born! Or Alexander Fleming notices a mold growing in a petri dish and suddenly penicillin transforms medical science.

Yet the truth is that the road to any significant innovation is a long and twisted path. First, scientific research uncovers important insights. Then, those discoveries must be engineered into useful solutions and finally, new products and processes must be implemented at scale in order to transform a particular field or industry.

Unfortunately, most efforts focus on only one part of the chain. Researchers toil away quietly in their labs, engineers tinker with improvements and evangelists work to accelerate adoption. Yet at MD Anderson they’re working on a new, more integrated model they hope will revolutionize the pharmaceutical industry. Early signs suggest that it’s working.

How An Insight Becomes A Blockbuster Drug

In 2014, 44 drugs were approved by the US FDA. Of those, McKinsey estimates that only one third will be successful in the marketplace. With some luck, a few may eventually become blockbuster drugs, the improbable runaway successes that finance the greater enterprise of drug development.

To understand why blockbuster drugs are so rare, let’s look at Immunotherapy, the miracle cancer cure that the journal Science designated as its breakthrough of the year in 2014. Early results show that it can extend the life of terminally ill cancer patients for years. Many go on to live normal lives, seemingly cancer free. It is nothing less than a miracle drug.

Yet it began not as a drug at all, but as an obscure discovery by some French researchers who, in 1987, found a previously unknown receptor called CTLA-4. An American scientist, James Allison, suspected that the discovery might be useful for fighting cancer and began to study it further. Nine years later he published his first paper, showing strong results with with mice.

Three years after that, in 1999, Medarex, a small biotechnology firm, bought the rights to the antibody, began drug development and was successful enough to be acquired by Bristol Myers Squibb. It still took another 11 years—or nearly a quarter century after the initial discovery—to complete clinical trials.

The FDA approved the new drug, marketed as Yervoy, in 2011. The treatment currently costs US$120,000.

The High Cost Of Failure

A six-figure price tag, despite the twenty-five year span of development, is shocking, even for a miracle cure. Yet with operating margins at 22%, Bristol Myers Squibb is far from outlandishly profitable (Apple and Microsoft, for example, both maintain margins of around 30%). What really drives the cost is the countless drugs that never make it to market.

Pharmaceutical firms which acquire the rights to a breakthrough idea like James Allison’s, first need to undertake Phase I trials to test for dose and toxicity, which costs about US$5 million. From there it goes on to Phase II, which seeks to find whether the drug may be effective. That costs an additional US$10-$30 million. About 55% of drugs make it past Phase II.

At this point, if the treatment fails, the company is out tens of millions of dollars with nothing to show for it. Drugs that pass through Phase II get the privilege of investing another US$100-US$250 million in Phase III, in which it must prove a demonstrable benefit over existing therapies (roughly half of all drugs fail in late stage Phase III).

So the remaining 5% of drugs, like Yervoy, must not only recoup the hundreds of millions of dollars it took to get to market, but also make up for the billions spent on countless failures. And many of the new revolutionary therapies are not for the mass market, but target the relatively small amount of people who have very aggressive, life threatening conditions.

A New Paradigm For Drug Discovery

In 2003, Ron DePinho, then a researcher at the Dana Farber Cancer Institute, started thinking about ways to reduce failure in drug development. It seemed to him that a large part of the problem lay in a lack of integration between biologists who do basic research, disease experts who design and perform clinical trials and drug developers like Bristol Myers Squibb.

As he investigated the problem further, he found that there were two main sources of failure. The first was that not enough research was done in the pre-clinical process before Phase I. The second was that all too often the drugs were targeted at the wrong medical conditions. In both cases, the result was millions of dollars in wasted investment.

When DePinho was hired as President at MD Anderson, he saw an opportunity to create a new paradigm for drug development. He brought in Giulio Draetta, a former Vice President at Merck and a top notch team of genetic and drug discovery researchers to found the Institute for Applied Cancer Science that would apply a cross-disciplinary approach.

The idea was that, rather than have separate teams of specialists pursue their work in peaceful isolation, they would create a true “team of teams” which would interact on a daily basis. That would allow them to perform greater due diligence in the preclinical phase, identify therapies with greater potential and target them at the right conditions.

So far, the results are encouraging. DePinho told me, “We’ve not only reduced the costs of getting to Phase I by about two thirds, but also to refine the concept of drugs already under development and, possibly most importantly, we’re killing off a majority of potential drugs that looked promising before we subjected them to greater scrutiny in the preclinical phase”

The Future Of Innovation Is Integration

The lack of integration in the pharmaceutical industry is by no means unique. Take, for example, the nearly mythical story about Steve Jobs visiting Xerox PARC in 1979. According to legend, the wily young entrepreneur had finagled an exclusive look at groundbreaking technologies, like the mouse and the graphical user interface, that led to the development of the Macintosh.

The truth is that he could have seen many of the same things in 1968, eleven years earlier, at a public presentation financed by the federal government. Now known as the The Mother of All Demos, it featured Douglas Engelbart’s vision of interactive computing, which led to the technologies that Apple later commercialized and made famous.

In just about every field, there are cloistered communities of researchers making potentially game changing discoveries that end up sitting on the shelf for years—or even decades. Clearly, we need to innovate the innovation process. We need to shift from a disjointed effort that puts researchers on one side of a great divide and industry on another, to a combined, interdisciplinary effort.

Thankfully, it seems like MD Anderson is not alone in seizing this approach. The current JCESR program at Argonne National Laboratory to develop next generation batteries and President Obama’s advanced manufacturing initiative are but two examples of programs that bring government, academia and the private sector together to create innovative solutions.

What these efforts have in common is that they put the problem first and build a collaborative effort around it. While it may be more romantic to believe in lone geniuses and flashes of insight, truly exceptional innovation is a team sport.

This article originally appeared at DigitalTonto.

Greg Satell is an internationally recognized authority on Digital Strategy and Innovation who has served in senior Strategy and Innovation roles for the Publicis Groupe, one of the world’s premier marketing services companies. In 2012, Innovation Excellence ranked Greg #6 on their annual list of the Top 40 Innovation Bloggers.

Previously, he was Co-CEO of KP Media and spent 15 years in Eastern Europe managing a variety of media businesses ranging from market leading web sites to history making news organizations to women’s and lifestyle focused media.