regenHU CEO: Bioprinting Will Strengthen OrganTrans Project to 3D Print Liver Organoid

The European consortium OrganTrans is preparing to develop a tissue engineering platform capable of generating liver tissue. The proposed automated and standardized disruptive alternative solution to organ donation for patients with liver disease will stand on 3D bioprinting know-how from Swiss biomedical firm regenHU. Coordinated by Swiss research and development center CSEM, the eight partners and two transplantation centers engaged in the consortium will be using regenHU’s 3D bioprinters to produce organoid-based liver constructs with organoid laden bioinks.

In April 2020, we reported that OrganTrans would tackle the important healthcare challenge of end-stage liver disease (ESLD) by capitalizing on advancements in the regenerative medicine field, like using biofabricated liver tissue, to develop an entire value chain from the cell source to tissue engineering, biofabrication, post-processing and testing, and liver transplantation under the “compassionate use exemption” regulation (which provides an important pathway for patients with life-threatening conditions to gain access to unproven human cells and tissue products). To understand the key role of biofabrication in this innovative project, asked regenHU’s new CEO, Simon MacKenzie, to tell us more about the challenges that lie ahead for the European consortium and his company.

regenHU CEO Simon MacKenzie (Image courtesy of regenHU)

The project officially began in January 2020, what can we expect when it ends in December 2022?

The current goal of this project is to create a functional biofabricated liver construct that can be implanted into a mouse model. I consider that the OrganTrans team will accelerate new solutions for patients with liver failure. It is challenging, but we do envision successful in vivo trials. Of course, this major achievement will not be the end of the story; significant work and research will still be required to transfer these results to human clinical trials. The major remaining challenges will probably be the process scale-up to produce larger tissue and regulatory aspects.

Will this research be groundbreaking to treat liver disease in the future?

Demonstrating the feasibility of the approach in a mouse model will be groundbreaking for the disease because it will demonstrate its potential as an alternative to transplantation. Diseases like NASH [nonalcoholic steatohepatitis, an aggressive form of fatty liver disease] are increasing dramatically, and likely to be a leading cause of death within the next few years. Moreover, the difficulty of detecting the disease until it is potentially too late leads to significant challenges for therapeutic intervention, meaning transplantation will remain the main option for severely affected patients. This well-recognized need, along with the lack of donor organs will ensure bioprinted livers will continue to be well funded. But the value of the project goes beyond liver disease, as the new technologies developed in the frame of OrganTrans will not be limited to liver applications. They relate to the challenges of biofabrication of any organoid-based tissue, which can potentially be beneficial for a large variety of indications.

Can you tell me more about the role of regenHU within the OrganTrans consortium?

Such a complex and ambitious endeavor needs very different and complementary knowledge and competences. Teamwork will be a central element, first to enable, then to accelerate, these new solutions. With this in mind, we have been reorganizing regenHU to bring better project collaborative capabilities to this project, and others like it that we are engaged in. regenHU is a pioneer and global leader in tissue and organ printing technologies converging digital manufacturing, biomaterials, and biotechnology to lead transformational innovations in healthcare. We focus on delivering advancements in the instruments and software required for tissue engineering, and our technology evolving along with the biological research of our partners. We, therefore, consider these partnerships with the scientific community critical for our development.

An outline of the OrganTrans project (Image courtesy of OrganTrans)

regenHU is one of the largest contributors to this project, is this part of the company’s commitment to regenerative medicine?

We can see the need for biotechnology solutions for a wide range of disease states. Our strengths are in engineering the instruments and software necessary to allow the producers of biomaterials and the suppliers of cells to combine their products to achieve functional tissues and organs. Our commitment is to provide disruptive technologies that will enable the community to make regenerative medicine a reality, with precision and reproducibility in mind, for today’s researchers and tomorrow’s industrial biofabrication needs. One of the key challenges is the current limitation in the scale and volume of bioprinting which is linked to the reproducibility of the print. To progress into the manufacture of medical products, bioprinters will need to operate at a scale beyond current capabilities. We design our instruments with these goals in mind and have assembled a team to solve the many challenges to achieve this.

How advanced is the bioprinting community in Europe?

The 3D bioprinting field is several years behind mainstream 3D printing, with the industrialization of the instruments, biomaterials, and cells required before bioprinting can progress to commercial-scale biofabrication. However, as with continued development seen in 3D printing, the technology convergence required for tissue and organ printing that changes medical treatments will become a reality through the efforts of engineering companies like regenHU, biomaterial developers, and human cell expansion technologies, being combined in projects such as OrganTrans.

As the newly appointed CEO of the company, how do you feel taking on this project?

Successfully entering the OrganTrans consortium is just one part of the company. regenHU investors see my arrival as the catalyst to bring regenHU to the next stage in its evolution. Our goal remains the production of industrial biofabrication instruments capable of delivering the medical potential of bioprinting, novel bioinks, and stem cells. To achieve this, we are enhancing the team and structure of the company, bringing forward the development of new technologies and increasing our global footprint to better support our collaborative partners. I have spent many years in regenerative medicine and pharma and can see the potential of bioprinting to revolutionize many areas of medical science, so joining regenHU was an easy choice. As CEO, my main role is to provide the right support structure to enable our entrepreneurial engineering teams to thrive and be brave enough to push boundaries. Additionally, as we cannot achieve our end goal on our own, I am here to nurture the important connections with our user community. Only by listening to their valuable insights and solving problems with them, we will push the technology onward.

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European Bioprinting Company regenHU is Paving the Way in Therapeutical Bioprinting

Nestled in the Fribourg countryside, amid medieval towns, deep mountain lakes, and Swiss-alpine traditions, bioprinting company regenHU (which stands for regeneration human) is developing some of the most advanced 3D printers in Europe and creating alliances with research institutions that are quickly making it a leader in this emerging field. Recent advances have given them the tools for fabrication of biomimetic tissue constructs, tissue growth technologies, and drug discovery. Just over a month ago, researchers at Tel Aviv University used regenHU’s 3DDiscovery printer to create cardiac patches and cellularized hearts for patients with heart failure, using patient-specific hydrogel as bioink, so as to avoid rejection. Working in multiple projects alongside their partners, such as the University of Glasgow, in Scotland; the United States National Institutes of Health, and the AO Research Institute in Davos, among others, regenHU is one of the go-to-bioprinting companies of the region. Looking forward to the next ten to twenty years, CEO and founder Marc Thurner is convinced that the future is in regenerative medicine and that their printers could make 3D printed implantable living organs a reality.

A pioneer in the bioprinting realm, regenHU’s story began in 2007 when bioprinting companies were just beginning to fill a much-needed void in the medical and research community. At that time there were three bioprinting companies, including San Diego-based Organovo. regenHU chose to exploit the potential of bioprinting in the therapeutical area and founded a unique corporate structure along with academic partners and affiliate companies which develop innovative transformational products into the medical environment. 

Thurner explained to that his “vision was to use additive manufacturing to create a three-dimensional biological environment in which to combine cells, bioactive and extracellular, like biomaterials in order to enable the cell to cell interactions and create physiological pathways that mimic the ones found in natural tissues and organs.”

At the time, as Thurner came around to that concept, the scientific community was still very skeptic about printing cells and proteins. “

“So regenHU had to face the difficult and resource consuming challenge to demonstrate cell printability and post-printing survival,” he said.

There were many other doubts, including whether the cells would be able to survive or even keep their morphologies. This was successfully achieved in 2009 and gave rise to a new industry of tissue printing. Still, the bioprinting industry is far from learning how all the applications of the machines work.

Marc Thurner, CEO & Founder of regenHU 

regenHU has done a lot to level the ground for bioprinting in Europe and overcome skepticism. Partnering with Ursula Graf-Hausner, a biologist and chemist specializing in tissue engineering cell culture technique at the Zurich University of Applied Sciences who was working with primary human cells and creating human tissue, looking to create the Tissue Engineering for Drug Development center at the university.

But dealing with live cells was no easy task, at first 3D printed cells did not survive, and although there were many cell-compatible biomaterials on the market, none of them solidified fast enough after printing. So the duo added biologist Markus Rimann, who had the idea of developing a chemically defined bioink, which made printing the material possible.

Since its start, the company has grown significantly, acting as a capital equipment provider and delivering cutting-edge bioprinting instruments to world-leading scientific and clinical institutions. Some of their clients include L’Oreal, Novartis Pharmaceuticals, among others. regenHU uses cells, proteins and extracellular matrix to make their biogels used in the creation of different tissue types, developing a unique knowledge about what ingredients and conditions are required to drive a specific tissue formation. This knowledge is the result of multiple research endeavors done along with academic and industrial research institutions.

“The evolution of biology is quite a slow process, scientists are still learning and understanding the basics behind the science. So our mission is to support their discovery providing dedicated scientific instruments. We hope that within the next ten years they will find the recipe to biomanufacturing simple tissue and believe that the future of bioprinting is in drug discovery, personalized medicine, precision medicine, and of course, organ transplant,” explained Thurner. 

regenHU bioprinter at work 

With more than 40 well-established bioprinting companies in Europe today, regenHU is still gaining ground. Furthermore, in an attempt to conquer the growing demand for dental 3D printing applications, regenHU together with the dental faculty at the University of Geneva created a spin-off company, Vivos Dental, to develop, manufacture and market oral bone augmentation solutions, like their patented OsteoFlux®, a 3D printed synthetic bone graft for oral bone augmentation and bone regeneration that is still in development. This could be a great option for patients who do not have enough bone volume for a dental implant, so Vivos Dental’s objective is to augment bone volume to offer a good attachment area. It’s an exciting time for dental 3D printing, especially as it is forecast to become an over four billion dollar market for dental prosthetics, orthodontic appliances, and other dental parts.

Bioprinting is no longer an early-stage technology, it has transitioned to the clinical environment, which is why regenHU developed 3DDiscovery Evolution, which is not just a bioprinter, it is a technology platform that can evolve with the researchers’ needs and offer optimal tools that can be integrated into a manufacturing process. RehenHu’s machines are being used to print skin patches for grafting onto burn victims, to develop muscle tissue models by pharmaceutical company Novartis, and even to print cartilage for joint repair.

regenHU software

A couple of years ago, regenHU realized that software technology is also a very important tool to enable bioprinting applications that would allow scientists to exploit their potential, so they invested in software tools, like BioCAD which allows researchers without an engineering background to draw in a layer-by-layer way the tissue they want to create, while BioCAM can import 3D data from medical scanners and modify structures for 3D printing.

As part of their expansion to new markets, clients and researchers, last year regenHU appointed San Diego-based lab automation solutions provider Wako Automation as its official systems integrator for the US.

3DDiscovery Evolution 3D printer

For regenHU, it’s all about contributing to the bioprinting industry by coordinating projects with academia, pharma users, biotech institutes and cosmetic companies that invest in these type of products. It’s part of their 3D discovery evolution and a way to learn how to control cellular biology to eventually develop some of the most sought after advances in regenerative and therapeutic medicine, like advances in biomimetic tissue constructs, to mimic an environment as close as possible to the in vitro situation.

Although having multiple collaborations around the globe and developing an ecosystem of partners and users are making waves within the biofabrication community, some areas, like developing vascularization to help create functional large organs is still challenging, so regenHU, like other bioprinting pioneers and leading companies, is looking for answers. It might take years before a big leap takes researchers to the next level in bioprinting.

[Images: regenHU]

3D Printed Paracetamol Tablets Have Big Implications for Personalized Medicine

Drugs affect everyone differently. That’s why it’s so hard to find the right medication and right dosage to treat people with depression, for example, or why certain people don’t seem to get much relief from painkillers. That’s why the prospect of 3D printed medication is so exciting. Companies like FabRx are working to create medicines with personalized doses through 3D printing. Not only does 3D printing allow for different medications to be combined in one dose, but, as a new study shows, dosages can also be customized to suit people with different metabolic rates. The study, entitled “Extrusion 3D Printing of Paracetamol Tablets from a Single Formulation with Tunable Release Profiles Through Control of Tablet Geometry,” was written by a group of researchers from the University of Nottingham and GlaxoSmithKline.

“Personalised medicine is defined as a customization of health care to individual patients through linking diagnostics and treatments with genetic testing and emerging technologies such as proteomics and metabolomics analysis,” the researchers state. “The main advantages of this approach are to increase the effectiveness of the prescribed treatment regimen and to minimise their adverse effects such as those linked to overdosing of drugs with a narrow therapeutic index such as digoxin and anti-clotting agents.”

Paracetamol, or acetaminophen, is one of the most commonly used over-the-counter painkillers, so the researchers selected it as the subject for their proof of concept study. Work has been done before using FDM 3D printing to formulate paracetamol tablets, they note, but the high extrusion temperature limits the potential active ingredients to only heat-stable ones. Other methods like SLA and ink-jet printing use excipients that are not generally recognized as safe, however, so FDM was chosen for the study.

A regenHU 3D bioprinter was used to print paracetamol into three different tablet geometries – solid, ring and mesh. The outer dimensions of the tablets were kept in the same oval shape, but the inner geometries were varied, as were the number of layers. The weights of the tablets were also kept consistent by varying their heights. The tablet surface area influenced the speed of the drug release – for example, with the mesh tablets, 70% of the drug was released within the first 15 minutes, while 25% was released from the ring tablets and 12% from the solid tablets in the same period of time.

Notably, each of the tablets contained the same dosage of paracetamol, but the different release rates meant that they would affect people in different ways. These release rates could, therefore, be tailored to specific patients’ metabolisms for the most effective treatment.

“The demonstrated ability to use a single unmodified formulation to achieve defined release profiles presents opportunities to optimise or personalise medicines during formulation development and in clinical use,” the researchers explain. “For example, relatively straightforward personalization of medicines would be possible for individuals with different metabolism rates due to their genetic makeup for certain drugs and hence could address issues where people who metabolise drugs slowly may accumulate a toxic level of a drug in the body or in others who process a drug quickly and never have high enough drug concentrations to be effective.”

Any drug is dangerous when taken in too-high doses, but some people tend to go overboard with painkillers such as paracetamol, because, as the researchers point out, they metabolize the drugs too quickly for them to be effective and thus think that more is better. More is toxic, in fact, but programming drugs so that their release rates are tailored to each individual’s metabolism means that the same dosage can be taken by different people and still have the proper effect on each one.

If this study could be applied to painkillers only, it would still be big news, but its potential goes beyond just paracetamol. Adverse effects could be minimized from drugs such as anticoagulants and antidepressants, even as they are tailored to be more effective to each individual patient. The prospect of personalized medicine through 3D printing has a lot of promise; one day we may look back on our current “one dosage fits all” standard as primitive medicine.

Authors of the paper include Shaban A. Khaled, Morgan R. Alexander, Derek J. Irvine, Ricky D. Wildman, Martin J. Wallace, Sonja Sharpe, Jae Yoo and Clive J. Roberts.

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