Shrinking gels and growing researchers

3D printing is one of the most promising technologies of today’s world as virtually any object can be made from scratch. The potential of 3D printing is immense for various industries: it could help astronauts to colonize Mars by printing the needed equipment on site, as much as it could help doctors to cure patients with organ failure by printing a new one in the lab. However, both astronauts and doctors would likely struggle with size. On Mars, entire buildings must be built, whereas in the lab, many structures must be microscopically small. Astronauts could fall back on other technologies like laser-jet cutters, but how should doctors overcome the printer’s resolution problem? Basically, there are two ways: either by improving the technology… or by shrinking the printed object.

While researchers and engineers around the world are trying to advance current 3D printing technologies, two researchers from the Utrecht Institute for Pharmaceutical Sciences travelled around the world to make 3D printed objects shrink. Carl Schuurmans (Division of Pharmaceutics) and Anne Metje van Genderen (Division of Pharmacology) visited Harvard Medical School, USA, to work on their project that has been published in Nature Communications. UU has covered their research here. For a glimpse behind the scenes, continue to read: we talked to Carl and Anne Metje to find out more about the big idea of making things small, and how they personally experienced their research stay at Harvard.

Hello Carl and Anne Metje! You work at different divisions and on different topics, but you were awarded a shared grant to work on shrinkable gels at Harvard. How did this collaboration take shape, and why did you go to Harvard for this?

Anne Metje: With Prof. Roos Masereeuw (Pharmacology) and Dr. Tina Vermonden (associate professor at Pharmaceutics), we share the same promotor and co-promotor, so we are aware of each other’s work. And thanks to the financial support of the Hofvijverkring, Dr. Shrike Zhang from Harvard Medical School was able to visit our labs last year to discuss potential collaborations. That’s how it all came together.

Carl: We presented him our discovery of shrinking gels, and together we saw the potential for applying this principle for 3D printing. Thanks to the MDR Young Talent incentive, Anne Metje and me were able to join his lab for 4 months. We brought complementary expertise to this project: I know how to make, process, and shrink the materials, and Anne Metje is studying cell-material interactions.

How do you make 3D printed objects shrink?

Carl: The concept is easy. The non-cellular component of the human body, also known as the extracellular matrix, consists of many different polymers and lots of water. In the lab, we can use polymers extracted from human tissue and modify them to form polymer networks, which are heavily negatively charged. These negative charges attract a lot of water, which makes the networks swell into gels that mimic the matrix of the human body. Recently, we discovered that if you introduce polymers with a positive charge into the gel, they interact with the network and cancel out the negative charge. In response to this, water leaves the gel – and the gel shrinks. By using this shrinking process, we were able to make 3D printed objects 10-12 times smaller in volume!

Now that you published the results that you obtained, how will you continue with this work in Utrecht?

Anne Metje: The shrinking worked well, but unfortunately we observed that most cells are too sensitive to survive the exposure to the shrinking reagent. For now, we can only use robust cell types, or we have to add the cells to the 3D printed object after shrinking. We are currently trying to find ways to better protect the cells from the shrinking reagent.

Carl: We are also further optimizing the shrinking method itself and perhaps we will find alternative ways of shrinking.

How did you experience your research stay at Harvard? What is the biggest difference between Boston and Utrecht?

Carl: For me, it was definitely a great experience to go abroad, and to Boston specifically. The area in and around Boston is a world-known hot spot for research institutes and start-ups. Utrecht has a very vibrant life sciences community, one of the best world-wide, but Boston is claimed to be part of the top in any research field. In that sense, it was an interesting environment to work in.

Anne Metje: I agree, the name Harvard attracts a lot of motivated and enthusiastic people who want to explore what is happening there. Boston has created a very rich research environment with several top universities and start-ups close to each other. Their work is truly interdisciplinary, and there are a lot of big events happening on a weekly, almost daily basis.

Carl: Yes, we could for example attend a course on the business side of regenerative medicine with speakers like Prof. George Church. The other week, we saw the current CEO of SpaceX give a talk on their new plans.

What does Utrecht have to offer, what Harvard doesn’t?

Carl: In Utrecht, the competition feels less fierce. I had the impression that the high density of high profile research in Boston hindered openness and accessibility. Here, it is much easier to benefit from each other’s knowledge and equipment. We have a lot of collaborations ongoing, especially between groups from Regenerative Medicine Utrecht. The question in Utrecht is never whether a collaboration is possible, but rather how both sides can benefit the most from it.

What do you consider the highlight of your stay?

Anne Metje: I did my internship in Boston before, so going back together with my husband was like returning to our second home. In the lab, it was very inspiring to work with extremely motivated undergraduate students. Most of them came from countries that cannot offer the same opportunities as Harvard. Going to Harvard is a unique chance which they definitely grab with both hands, to make everything out of it. I really liked to experience this spirit.

Carl: Me too. To my own surprise, I also liked the American spirit. Their enthusiasm about everything is often labeled as exaggerated, but to me It seems they really are genuinely enthusiastic. Americans are very approachable. And in the lab, when a manuscript has been reviewed for publication, everyone dropped their own project to contribute to the rebuttal. That level of cooperation in a lab is very nice to experience.

Bioprinting is a young but promising field. How do you envision Regenerative Medicine in 10 years?

Carl: Bioprinting has reached quite some milestones already. We can print physiologically relevant structures, fast, accurately, and reproducible. The crucial next step is to get functional tissue. Researchers from Regenerative Medicine Utrecht have recently published a very nice review about this matter, which I think sums up the open challenges nicely.

When, do you think, will patients benefit?

Carl: Personally, I cannot estimate how feasible 3D bioprinting will be for clinical use. For us, it is above all a steep learning curve about how cells, materials and molecules interact on the microlevel; how can you guide a few hundred cells  to grow into a specific tissue or (mini-)organ?

Anne Metje: Clinical feasibility also depends on the organ of interest. Some organs are very complex, perhaps too complex for bioprinting. Other organs and tissue are more simple, and here, we can observe quite some successes already, also in Utrecht.

Obviously, your research abroad has been valuable for you, both on professional and personal level. Do you have any advice for your peers?

Anne Metje: For sure, I would recommend a stay abroad during your PhD. The experience of doing research in another lab and culture can help you to put things into perspective. At the same time, it is a lifetime experience, and good for your career and network.

Carl: And it is fun! My advice would also be to not do everything by yourself. We still like the traditional idea of a single scientist working isolated on a project for 4 years, with a book as final outcome. However, more collaboration can lead to much stronger science.

Very good advice! Thank you both for your time!

The project has been funded by the MDR Young Talent Incentives Program, the Hofvijverkring, the NWO Future Medicines Program, and the Dutch Kidney Foundation.

This blog is written by Katja Jansen (RMU communications officer (2019-2020) and PhD candidate in Drug Innovation (2016-2020)).