BeNeLuxBiofabricationBioprintingEditorials

Utrecht, a biofabrication wonderland

A voyage through one of the most vibrant bioengineering communities in the world

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A wonderland, by definition, is a land or place full of wonderful things; when it comes to the sector of biofabrication, this is true for the city of Utrecht. This opinion editorial is a tribute to my almost three years in Utrecht and all of the innovators, start-ups, and colleagues that have inspired or guided me. The irony is I write this article thousands of miles away at the Chateau Marmont in Los Angeles, a hotel famous for writers such as F. Scott Fitzgerald, Hunter S. Thompson, and many other authors, musicians, actors, and novelists over the years. Led Zeppelin drove their motorbikes through the lobby, rumors that Jim Morrison jumped out of a balcony, and here I am in silence next to a vintage record player researching content, reliving years of memories, and drafting an article about a biofabrication wonderland that can be found in the city of Utrecht. I also write this article as I fully return to the life of a biofabrication entrepreneur in 2022. I have learned more from failures than successes during my career whether in academia, consulting, or start-ups. Failures have happened so often in my career that I cannot count them anymore. I have learned some important skill-sets over the years; to remain positive, focused on the future, surround myself with deep technology innovators in Utrecht, and never give up.

The Chateau Marmont, Hollywood, Los Angeles, California. Photo Credit: Chateau Marmont

The entire reason I got into the field of regenerative medicine over a decade ago was to find cures or solutions to treat neural diseases that family members have experienced such as Parkinson’s disease and Depression. Now I can do that with the innovative biofabrication start-ups I helped to co-found in Utrecht in early 2020: Ourobionics BV and GutsBV. Both start-ups will play a vital role surrounding the recent discoveries of the importance of the gut-brain axis with a need for more physiologically relevant 3D biofabricated neural and gut models. GutsBV has developed a complete physiologically relevant 3D human intestinal model with all of the important cellular components so this is truly transformative biofabrication technology for future use to reduce and replace animal testing.  Also, to cure neurodegenerative diseases we need to enhance the development of four-dimensional minimally invasive, self-powered, induced pluripotent stem cell and cyborganic brain stimulation and regenerative devices connected to disease biomarker skin sensors. The technologies within Ourobionics are making this closer to reality. Bioelectricity has been identified as a key factor for tissue regeneration and reversal of the aging process (3). This indicates that some of Ourobionics‘ novel technologies such as manipulation of electric, magnetic, and electromagnetic fields with cyborganic biomaterials could revolutionize biofabrication & regenerative medicine. The novel biofabrication and cyborganic technologies have been proven for the creation of 3D models but innovative advancements for 4D human-machine interfacing could now be possible to regenerate and maybe one day reverse aging in the body.

A voyage through Utrecht, a biofabrication wonderland and one of the most vibrant bioengineering communities in the world
GutsBV’s 3D biofabricated Intestinal model shows a significant decrease of inulin-FITC permeability after the 21-day cultivation protocol4. The presence of enterocytes is shown by alkaline phosphatase activity. Goblet cells, enteroendocrine cells, Paneth cells and stem cells presence were shown by immunofluorescent staining for mucin-2, chromogranin A, lysozyme and leucine-rich repeat-containing G-protein coupled receptor (5), subsequently. Finally is the presence of villi-like structures shown by a top and side view of the bioengineered intestinal tubules (4).

“I believe it all starts with the eagerness to learn, grow and generate an impact. The process of linking science and business is challenging because different mindsets are required. National and regional opportunity allowed me to develop and add the “business-mindset” to my skill set”Dr. Paul Jochems, Founder and Chief Executive Officer, GUTS BV

They say that some cities steal your heart. For me, Utrecht is one of those iconic cities that captures your soul and you never want to leave. I can’t describe it in so many words, but it has somehow inspired the continuation of my journey in biofabrication start-ups. Everyone needs to at least one time experience the pure joy and inspiration that comes from cycling along the breath-taking canals between meetings with scientists, engineers, fellow entrepreneurs or a drink with a colleague in this industry. There are no words to describe the pure joy of life in this innovative city I call home. I have been lucky to go on multiple walks with the managing director of Utrecht Science Park, Jan Henk van der Velden, and his dogs while he explained the history of the region and plans for the future within life science and sustainability. Jan Henk van der Velden and Friso Smit are two great leaders at Utrecht Science Park that have inspired me for almost 3 years and make sure the USP remains a great location for start-ups, scale-ups, medical professionals, students, and academics alike. I would be lying if I said the life of an entrepreneur had never taken a toll on my mental health, but the development of a high level of endurance and resilience from these past experiences has given me extra strength to be a successful deep technology entrepreneur in recent years. Something about Utrecht Science Park revitalized my entrepreneurial spirit and made me revisit going full throttle in the world of 3D/4D Biofabrication in 2022.

I fondly remember when Jan Zuidema, and Friso Smit, two former managers, somehow managed to rebuild and mentor the entrepreneur within me by embedding me within the entrepreneurial ecosystem and hubs at Utrecht University to help students and professors become entrepreneurs. The founder and CEO of Humabiologics Inc. also played a vital role in bringing the entrepreneur within me back to life and he too was very interested in connecting to Europe via the city of Utrecht.

The first young scientist entrepreneur I met was Dr. Paul Jochems in late 2019, early 2020. At that time, he was finishing up his Ph.D., and Friso connected us to discuss building a start-up surrounding his 3D biofabricated intestinal model that had some fascinating results for analyzing the nutritional compounds and the gut barrier integrity. Paul and I spent many times over coffee and beers taking the research out of the academic mindset and into an entrepreneurial perspective. Paul didn’t have anyone to co-found his start-up with, so I joined him as a co-founding advisor and guided him on building his management team5.

Within a couple of months in start-up mode, Paul was awarded approximately 220,000 EUR in funding to develop his start-up www.gutsbv.com. He was accepted into the national Venture Challenge, where I joined him as his core team member while building, and needless to say, we had a great time in the company of other Dutch entrepreneurs such as medical VR. Since then, Paul has gone from strength to strength and has a solid team to offer a service where clients can use his healthy and diseased intestinal models to replace the use of 2D transwells and animal experiments. He has a database of results that he is improving into more of an interactive artificial intelligence platform that can connect to the data from the intestinal model

It is a common unspoken factor of the entrepreneurial mindset that is often overlooked, but this mindset is essential for success. A recent article suggests this about the entrepreneurial mindset “We now recognize that the value of creative capital exceeds that of traditional capital such as money, land and raw materials.” (6). As the Netherlands is experiencing another hard lockdown while writing this article, it is essential to remember that “Happy Entrepreneurs are more mentally well, more emotionally stable, and more likely to launch grow and sustain businesses” (6). It is an interesting article as it showcases Elon Musk and how he has achieved so much while overcoming aspects of mental health such as Asperger’s and Bipolar (6) to achieve more than most in any industry. I can also relate to him from an interview where he spoke about how he thought it was normal to have a mind with a never-ending explosion of ideas and insights. So, what do we do? How do we protect our valuable assets and keep our entrepreneurs happy, stable, and prosperous?

“We need to exploit our scientific excellence far more than we are currently doing. The likeliness of a scientist founding a start-up remains very low. That is why the Faculty of Impact program provides PhDs with two years to explore and develop their idea” Prince Constantijn Van Oranje-Nassau; Envoy at Techleap.nl; co-founder of StartupFestEurope

Utrecht Science Park does precisely this; it keeps entrepreneurs from all walks of life happy. It has a thriving ecosystem filled with start-up incubators like Utrecht Inc, affordable laboratory space for start-ups at the iLab in the Hogeschool Utrecht, and access to some of the best research and medical minds in the world Utrecht University and one of the top global hospitals University Medical Centre Utrecht. Not only that, the ability to cycle from your home in Utrecht to the Science Park is an excellent form of stress relief. I don’t think you ever need a car in the Netherlands; they have made cycling efficient.

How would I describe Utrecht Science Park? If you have ever visited Cambridge in Boston (home of Harvard and MIT), I would make that direct comparison. It is easy to access via cycling, an efficient tram, or bus transport system. It has every resource and facility imaginable. When you walk around USP like Cambridge in Boston, you can bump into a high-impact professor, a daring young entrepreneur, or a passionate student. Did you know that if you have an idea for a start-up as a Ph.D. student there is a new fund launched by TechLeap; Faculty of Impact; that gives students access to 200,000 EUR in funding and access to mentors for two years.

“Some great magic is happening at USP. UtrechtInc is one of the leading university linked business incubators in the world and it our honorable duty to connect and accelerate entrepreneurial scientist in our network“Jorg Kop, Managing Director of Utrecht Inc

A voyage through Utrecht, a biofabrication wonderland and one of the most vibrant bioengineering communities in the world
Utrecht Science Park, Utrecht, The Netherlands. Photo Credit: utrechtmarketing.nl

From Utrecht, you can get to almost any city within the Netherlands within 45 minutes by train. If you want to get to Paris, London, Brussels, Dusseldorf, it is a maximum of four hours (ideal for your start-ups BD team). An additional reason to choose the Netherlands as your location for a biotechnology start-up is that it ranks 3rd globally when you combine world competitiveness rankings, world innovation rankings, human development index, and the world happiness report.

As this article is focused on biofabrication, most people within the Netherlands are aware of the enormous successes of Prof. Jos Malda in 3D Bioprinting and Prof. Hans Clevers- the godfather of organoid technologies. It is also home to one of the core global organoid hubs, the Hubrecht Institute and the spin-out company Hub-Organoids. Organoid technology is of huge importance to any researcher, clinician or start-up in the field of regenerative medicine as it has the potential to bridge the gap between conventional 2D cell culture and reduce or replace animal models. The near-physiological 3D biofabrication technology can recapitulate organ development and human diseases, such as infectious diseases, genetic abnormality and even cancers (7).

If you walk into Prof. Malda’s lab, you will see a facility of almost every bioprinter imaginable and even more innovations surrounding the development of more advanced technologies such as volumetric and electric field biofabrication. Many of the following cutting-edge innovations within the world of biofabrication are coming from Jos’s lab and his work with the expert team of Dr. Levato and Dr. Casthilio. In 2020 Prof. Malda’s group was awarded funding to build an even stronger biofabrication GMP facility as part of a national growth fund initiative. The Malda group were part of a 56 million Euro national growth fund with RegMedXB It is a collaboration between research institutions, governments, provinces, health funds and the business community of the Netherlands and Flanders to develop therapies for chronic diseases based on stem cells, mini-organs, tissues and smart (bio) materials (8). It involves the development of a pilot plant for regenerative medicine which does not only contribute to healthcare but also means increasing the innovative strength of the Netherlands to continue the countries strength as a forerunner in Regenerative Medicine. More than 12 million EUR of the promised amount will go to Utrecht to support the development of an Innovation Center for Advanced Therapies (ICAT) (8).

Prof. Bart Spee and Dr. Kerstin Schneeberger, Co-founders of Orgonex

The center brings together all relevant expertise and infrastructure for the development of regenerative treatments and disease models using biofabrication and 3D bioprinting. Personalized therapies and clinical studies are partly developed on the basis of immune cell, stem cell, and organoid technology, in Utrecht which is a forerunner in this sector (8). Friso Smit played a vital role in this project, I witnessed him work non-stop to make it a success. An additional benefit of the region is the ability to get proof of concept investment (250,000EUR) as a start-up from the Utrecht Health Seed Fund and the ROM Utrecht Region. The ROM also has investor readiness programs and a larger participation investment fund for the next rounds of investment.

Similarly, for Prof. Bart Spee and Dr. Kerstin Schneeberger, I guided them in the direction they needed to go for their early-stage start-up, Orgonex (9). They have gone from strength to strength, from being part of the Utrecht Inc start-up validation program to the national venture challenge in the Netherlands. Bart and Kerstin have invented an organoid bioreactor that can enhance their function and scale their use for more high throughput applications. If organoids are the gold rush in biofabrication then bioreactors are the shovels was a great quote I recall from our first meeting at Utrecht Inc. Both start-up ventures emerged from my assistance of the Utrecht Advanced In Vitro Model Hub at Utrecht University, led by the highly innovative Prof. Roos Masereeuw and Prof. Jos Malda.

Entrepreneurial skills are not standard in the portfolio of academics, but with all the support from business developers and courses including Utrecht Inc at Utrecht Science Park, we made a flying start with our venture and are looking forward to build on this.Bart Spee, Associate Professor Veterinary Medicine

The FelixBio bioprinter.

In June 2020 of the same year, I got an email (that I will frame) from John Zandbergen to my Imperial College London account. At that time, John had his successful consultancy and was helping the company Felix Printers, also based in Utrecht, expand their new affordable bioprinter into the market. The FelixBio is one of the most cost-efficient machines on the market, which I think is vital to allow researchers to gain access to entry-level technologies within the tissue engineering space. When John and I met in Café Hemingway in June 2020, he explained his interest in the industry. I gave him all of my background knowledge on what needed to be done in the industry, my unpublished technology inventions at Imperial College London. I gave my insight on how more advanced 3D and 4D biofabrication technologies were needed to overcome the many limitations of extrusion-based bioprinting. In my opinion, extrusion technologies are too slow, damage cells, and never create high throughput human models to replace animal experiments. That was the inception point or the moment Ourobionics was co-founded in Utrecht. Due to my work commitments, I could only be a co-founding advisor to Ourobionics BV. Still, I built the expert management team around him from multiple professors in my network with a passion for building start-ups that utilized their technologies.

I won’t’ go into too many details. You can refer to my two previous editorials at 3D Printing Media Network for more information on Ourobionics and its ground-breaking technologies. They have the potential to disrupt one industry and start to build new industries. My two editorials are entitled: “Is it the end of extrusion bioprinting for realistic applications in regenerative medicine” and “The rise of 4D bioprinting and cyborganics: next generation human-machine interfaces, regenerative medicine, and medical devices“. Both start-ups can match with the EU’s need to end animal testing.

In conclusion, the future of biofabrication could potentially be led by the innovative city of Utrecht. From my own personal perspective, I am interested to be a vital cog in the wheel of this biofabrication innovation within all of the Netherlands and want to build a start-up and research bridge or trinity between the Netherlands, Ireland, and the United States of America. The countries are already global leaders in research into biofabrication and regenerative medicine so an alliance makes sense. There is a strong match between the entrepreneurial cultures and ecosystems with each one requiring something from the other. The logo of Ourobionics is a mix of Irish and Dutch colors to symbolize the strong partnership between founders in this sector.” It is one of my visions to inspire and build more entrepreneurs in all sectors of life sciences and biotechnology or deep technology as it is often referred to now.

This article is dedicated to the memory of my uncle John Gray (January 2022), thank you for some of my best childhood memories. The legend of CúChulainn10 lives on through BV building start-ups and deep technology innovation.

Sources:

1.         Tatler Chateau Marmont, the wildest hotel in Hollywood, to begin new chapter as private members club. https://www.tatler.com/article/escape-to-chateau-marmont-hollywood (2020).

2.         Cellophaneland Chateau Marmont-Los Angeles. https://www.cellophaneland.com/travel/chateau-marmont-los-angeles-2/ (2020).

3.         Yorker, N. Persuading the Body to Regenerate Its Limbs. https://www-newyorker-com.cdn.ampproject.org/c/s/www.newyorker.com/magazine/2021/05/10/persuading-the-body-to-regenerate-its-limbs/amp (2021).

4.         Jochems, P.G.M. et al. Development and validation of bioengineered intestinal tubules for translational research aimed at safety and efficacy testing of drugs and nutrients. Toxicology in Vitro 60, 1-11 (2019).

5.         Paul Jochems and GutsBV. https://www.uu.nl/en/background/how-phd-candidate-paul-jochems-is-valorising-his-research (2020).

6.         Life, N. The brain of an Entrepreneur. https://neo.life/2021/12/the-brain-of-an-entrepreneur/ (2021).

7.         Xu, H. et al. Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine. Exp Hematol Oncol 7, 30-30 (2018).

8.         University, U. Regenerative Medicine Growth Fund awarded. https://www.uu.nl/nieuws/56-miljoen-euro-uit-nationaal-groeifonds-voor-regmed-xb (2021).

9.         Bart Spee and Orgonex. https://www.uu.nl/nieuws/how-to-create-an-organoid-bioreactor-and-how-to-market-it-interview-with-dr-bart-spee (2020).

10.       BBC Cuchulainn: The Hound of Ulster. https://www.bbc.co.uk/legacies/myths_legends/northern_ireland/ni_7/article_1.shtml.

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Dr. Stephen G. Gray

Dr. Stephen G. Gray is a serial entrepreneur with 10+ years of experience in biomedical engineering, regenerative medicine, & deep technology. He has co-founded multiple start-up companies: Ourobionics, Cartallum, Cybosense, GutsBV, OuroFoods, & Nukaryo. The start-ups focus on transforming different sectors: 4D Bioprinting, Human Machine Interfaces, Regenerative Medicine, Blockchain, Food, Textiles, Biorobotics, Space, Organ on a Chip, & Industry 4.0. The first start-up he co-founded, Ourobotics, was voted amongst the Top 10 3D bioprinters in 2015 & they open-sourced basic extrusion 3D bioprinting in 2016. He co-founded the writing style of "Ouro Journalism" with a focus on the sector of deep technology & longevity. He is based in Utrecht, the Netherlands and is a bioengineering PhD alumni of a top 10 global university: Imperial College London.

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