TissUse establishes a liver-endocrine tissues multi-organ model for risk assessment with Bayer

Berlin, September 2018. TissUse has signed a collaboration agreement with Bayer to develop a highly innovative liver-endocrine tissues assay using TissUse’s Multi-Organ-Chip (MOC) technology.

Under the terms of the collaboration agreement, TissUse will join forces with Bayer to develop a novel mechanistic in vitro assay that will allow assessment of species differences of critical toxicities for early development and registration.
Furthermore, the new assay is expected to significantly contribute to the 3R principles of animal welfare.

MOC-based liver-endocrine tissues assay to bridge the gap between animal and human safety assessment

The assessment of human relevance of certain toxicities observed in animal assays still represents a major challenge for the various areas of toxicology (human & veterinary drug candidates, agrochemicals and industrial chemicals). A recurring problem is thyroid or testicular toxicity that occurs in both crop protection, as well as human and veterinary drug development candidates. Answering whether toxicity findings in rodent lack human relevance as well as predicting human toxicities that are absent in rodent are key for risk assessment and regulatory success.

The project aims to establish a Multi-Organ-Chip based assay combining the target organs and liver in an integrated microfluidic system allowing for metabolic and endocrine interaction. This will enable researchers to differentiate between direct effects on the target tissues and indirect effects mediated by liver activation using an in vitro assay.

“We are thrilled to start this new collaboration which will address a fundamental area of unmet need in safety assessment,” says Dr. Uwe Marx, CEO of TissUse. “We already have a long-standing relationship with Bayer and this new project will enable the development of an assay with potentially great predictive power for Bayer across divisions and businesses.”

About the Multi-Organ-Chip (MOC) technology

TissUse proprietary commercial MOC technology platform is a microfluidic microphysiological systems platform capable of maintaining and culturing miniaturized organ equivalents emulating the biological function of their respective full-size counterparts over long periods. Major features of living biology such as pulsatile fluid flow, mechanical and electrical coupling, physiological tissue-to-fluid and tissue-to-tissue ratios are incorporated. This supports the development of a large variety of substance test assays ranging from acute and repeated dose toxicity to long-term disease treatment (efficacy). The technology allows for flexible and customized combination of different tissue constructs or organ equivalents on a disposable chip-based microphysiological system. The number of organ equivalents supported by the platform ranges from single organ culture up to an organ number supporting the study of complex organ interactions. First commercially available platforms support single-, two-, three and four-organ culture. Examples of organ models available at TissUse include: liver, intestine, skin, vasculature, neuronal tissue, cardiac tissue, cartilage, pancreas, kidney, hair follicle, lung tissue, fatty tissue, tumor models and bone marrow. Further organ models are being developed. The platform further comprises Control Units operating up to four MOCs simultaneously. These Control Units provide the flexibility needed to control and monitor any on-chip organ arrangement. Some of the existing models include different levels of immunocompetence such as immune cells in skin biopsies, Langerhans cells in full-thickness skin equivalents, hematopoietic progenitor cells in the bone marrow model and Kupffer cells in liver spheroids.

TissUse reports progress made in collaboration with AstraZeneca to use Microphysiological Systems in the drug development process

Berlin, 22.01.2018 - TissUse continues their successful collaboration with AstraZeneca to establish relevant Microphysiological System (MPS) models based on TissUse’s Multi-Organ-Chip technology.

As part of the collaboration, the teams have explored the unmet need for a physiologically relevant human ex-vivo type 2 diabetes model.  The result was a human microfluidic two-organ-chip model to study pancreatic islet–liver cross-talk based on insulin and glucose regulation for up to 15 days in culture.  This work was recently published in Nature Scientific Reports (Bauer et al., 2017, doi:10.1038/s41598-017-14815-w). Dr Tommy Andersson of AstraZeneca will present the data at the 3D cell models congress in Berlin on 24-25 January 2018. 

TissUse and AstraZeneca continue to work together to further develop this into a comprehensive type 2 diabetes-on-a-chip model.

TissUse’s Multi-Organ-Chip technology emulates multiple interacting human organs on a device the area of a microscope slide to imitate the complex processes in the human organism over both short and long periods of time. This technology is envisioned to clarify how the human organism reacts to new medication, cosmetic substances or chemicals without expensive animal testing.

“Miniaturized human Multi-Organ systems are capable of generating crucial, unprecedented data during preclinical assessment of drug candidates and are expected to increase success rate in drug development. We are happy to be able to support AstraZeneca in their aim to bring innovative medicines to patients worldwide,” says Dr. Uwe Marx, CEO of TissUse.

There is great potential for the innovative multi-organ-chip technology to enhance our approaches in drug development. Our collaboration with TissUse enables us to utilise the technology to advance our understanding of the biological control in key unmet disease areas such as type-2 diabetes. We look forward to the results from the advanced model that is currently under development,” said Dr. Regina Fritsche-Danielson, Head of Cardiovascular and Metabolic Diseases at AstraZeneca’s IMED Biotech Unit.

New joint research project investigates neurodegenerative aspects of Alzheimer's disease

(Berlin, 05.09.17) The interdisciplinary consortium HiPSTAR tries to decipher the molecular mechanisms leading to Morbus Alzheimer. In particular, pathological alterations at the blood-brain-barrier are in the focus of this applied research project. The long-term goal of this collaborative effort is the development of new drugs and therapies targeting this predominant form of dementia. The project is coordinated by the University of Würzburg (Medical Faculty, Department of Tissue Engineering and Regenerative Medicine, TERM), and TissUse GmbH, is a partner in the consortium. The German Ministry for Education and Research (Bundesministerium für Bildung und Forschung, BMBF) funds this project with an overall budget of 1.7 million Euro.

In order to decipher the molecular mechanisms leading to Morbus Alzheimer and associated changes at the blood-brain-barrier the German Aerospace Center (Deutsches Zentrum für Luft- und Raumfahrt e. V., DLR) funds this interdisciplinary research project with an overall budget of 1.7 million Euro over a three year period.

The acronym HiPSTAR is short for “Human iPS Cell-based Blood-Brain Barrier Technology in Alzheimer Research“ and is coordinated by the Department of Tissue Engineering and Regenerative Medicine (TERM) of the University of Würzburg. The consortium consists of academic partners and small and medium sized enterprises (see below). HiPSTAR is part of the BMBF initiative “directive on the promotion of innovative stem cell technologies for individualised medicine”.

Working hypothesis: Altered blood-brain-barrier is a prerequisite for the development of Alzheimer´s

"The development of new drugs requires more detailed research and understanding of the exact causes of neuronal degeneration in the brain”, Dr. Marco Metzger explains. The coordinator of the HiPSTAR project at TERM continues: "In addition, we assume that an altered blood-brain-barrier plays an essential role in the development of Alzheimer's disease and also worsens the prognosis of the disease". The blood-brain-barrier is a protective barrier between the sensitive brain and the blood circulation.

Goal: Establishment of an in-vitro model of the blood-brain-barrier

The aim of the research project launched at the beginning of February this year is to develop a new in vitro model of the human blood-brain barrier specifically for Alzheimer's research. Dr. Metzger explains: "This model will serve as a research tool for the development of improved diagnostic methods, the identification of suitable target structures for treatment and the discovery of cellular mechanisms of the disease.” The cells required for the model either originate directly from Alzheimer's disease patients or are artificially generated in the laboratory using molecular genetic methods, so that they carry the known mutations of Alzheimer's relevant genes. By applying microfluidics to mimic vesicular blood flow and disease-specific molecules the laboratory setting will be customized to the “real” situation within the patient´s brain. The newly established models will be validated with approved and marketed drugs and compared to conventional models currently applied in pharmaceutical drug development. In addition, the researchers are also developing a computer-based model to identify cellular target structures and predict the effects and transport properties of drugs at the blood-brain barrier.

The HiPSTAR consortium consists of:

• University Würzburg, Medical Faculty, Department of Tissue Engineering and Regenerative Medicine (TERM),
• Fraunhofer Institute for Molecular Biologie and Applied Ecology IME (ScreeningPort, Hamburg; www.ime.fraunhofer.de),
• University Halle, Medical Faculty, Department for Psychiatry, Psychotherapy and Psychosomatic Medicine (www.uk-halle.de),
• TissUse GmbH (Berlin, www.tissuse.com),
• Pharmacelsus GmbH (Saarbrücken, www.pharmacelsus.de),
• Insilico Biotechnology AG (Stuttgart, www.insilico-biotechnology.com),
• Austrian Institute of Technology (AIT) GmbH (Vienna/Austria; www.ait.ac.at).

The principle of producing blood-brain-barrier models from Alzheimer's disease patients: In the first step, cells from tissue biopsies of Alzheimer's disease patients are isolated. In a second step, these cells can be used to produce pluripotent stem cells (iPS cells), which are differentiated in the laboratory into specialized cell types of the blood-brain barrier. The blood-brain-barrier models produced from these cells are used by scientists to investigate the mechanisms of Alzheimer's disease and to develop appropriate treatment strategies. (Source: TERM)

ProBioGen grants a license for human lymph node technology to TissUse for Multi-Organ-Chip applications

ProBioGen AG and TissUse GmbH have signed a license and cooperation agreement to integrate ProBioGen’s Human Artificial Lymph Node Model into the Multi-Organ-Chip technology of TissUse. With the Lymph Node Model direct effects of substances on the human immune system can be monitored. The Multi-Organ-Chip technology emulates multiple interacting human organs on a device, not larger than a microscope slide, to imitate the complex processes in the human organism over periods of up to two months. This technology is envisioned to explore how the human organism reacts to new medicines, cosmetic substances or chemicals without expensive animal testing. TissUse now licenses the patented Lymph Node Technology Platform (HuALN) from ProBioGen and thereby expands the range of applications of Multi-Organ-Chip technology to predictions of immune reactivity in interaction with other organs.

“The combination of ProBioGen’s unique HuALN model and our human Multi-Organ-Chip technology will in future initially allow for the analysis of immunological reactions of human organs on active substances. Disease mechanisms in systemic autoimmunological diseases, allergies and anti-tumoral reactions will be elucidated with such Multi-Organ-Chip systems,” explains Dr Uwe Marx, CEO of TissUse.

“This partnership will bring together two highly motivated teams with a wide scope of experience and comprehensive know-how. We look forward to a fruitful collaboration increasing the scope of applications for our artificial lymph node system to allow its use for even broader pharmaceutical applications,” says Dr Wieland Wolf, chairman of ProBioGen.

About ProBioGen AG www.probiogen.de

ProBioGen is a specialist in the development and manufacturing of complex therapeutic glycoproteins. Combining state-of-the-art development platforms together with intelligent product-specific technologies yields biologics with optimised properties.

Rapid and integrated cell line and process development, comprehensive analytical development and reliable GMP manufacturing is performed by a highly skilled and experienced team. All services and technologies are embedded in a total quality management system to assure compliance with international ISO and GMP standards (EMA/FDA).

ProBioGen has been operational for more than 20 years and is based in Berlin, Germany.

About the Human Artificial Lymph Node (huALN) Model

www.probiogen.de/innovative-technologies/human-immunogenicity-immunofunction.html

The proprietary and unique Human Artificial Lymph Node Model (HuALN) was developed by ProBioGen as superior 3D micro-organoid model for analysing substance effects on the human immune system in vitro. It is based on a patented, miniaturised and perfused bioreactor for the long-term cultivation of immune cells. Human blood-derived dendritic cells, T and B lymphocytes and mesenchymal stem cell-derived stromal cells are inoculated into the bioreactor’s 3D hydrogel matrix, which is perfused with cell culture medium and aerated, just as in a real human lymph node. Upon antigen-stimulation, the cells self-organise into immune-competent micro-organoid structures within the 3D matrix. The perfused bioreactor is typically operated for four weeks and, thus, allows multiple and repeated exposure of the immune cells to the test compounds.

This innovative technology predicts drug-related effects – wanted or unwanted – on the human immune system. The HuALN Model allows the specific investigation of immunofunction, such as immunomodulation, immunogenicity and immunotoxicity, in vitro. A broad range of substance classes, from small molecules, proteins and peptides to nucleic acids, can be tested, covering biopharmaceuticals, vaccines and cosmetics.

The read-outs are on the T and B cell level, looking specifically at cytokine profiles, cell surface makers, cell proliferation, IgM and IgG secretion, anti-drug antibodies (ADA formation) and functional cell tests.

The huALN technology is offered by ProBioGen as a service and can be licensed to third parties.

TU Berlin and National Institutes for Food and Drug Control (NIFDC) China extend their cooperation in regulatory science.

Development cycles in the markets are accelerating. Regulatory authorities worldwide continuously face the challenge of declaring new drugs, cosmetic ingredients and food products as harmless to health. They make their decisions based on data provided by manufacturers. However, frequent setbacks in clinical studies prove how inadequate these data can be. Since 2014, the National Institutes for Food and Drug Control (NIFDC) China rely on regulatory science and early control in the approval process. TU Berlin now enables NIFDC to engage even more in the scientific aspect of the approval process as both organisations have extended their cooperation to six years. The first Chinese scientists recently finished their training in the operation of Multi-Organ-Chips (MOC) in Berlin. Now the technology will be transferred to China, where the scientists of the institute will be trained to independently execute tests.

“This makes NIFDC the first authority in the world to test the Multi-Organ-Chips independently and to use this technology with self-established assays to intervene in the development cycle”, explains Uwe Marx, inventor of the technology and CEO of TissUse GmbH founded as a spin-off of the TU Berlin in 2010.

The Multi-Organ-Chip technology currently makes it possible to replicate up to four human organs, scaled down 100,000 times, from cell tissue on a microscope slide. They are connected to each other with a system similar to blood vessels. Micro valves replicate the heart and the cell structures react to administered substances just like a human organism.

Experiments for testing new drugs, cosmetic ingredients and chemicals thereby do not need animal testing any more and developers as well as regulatory authorities can test how humans react to specific substances over longer periods of time. According to Marx, the use of human cells also allows the results to be transferred more easily than data from animal testing.

About TU Berlin

The Technische Universität Berlin (TU Berlin) is one of the oldest technical universities in Germany. With more than 32,000 students in 100 degree programmes, the university ranks among the largest universities in Germany. In addition to the university’s faculties and institutes, there are numerous collaborative research centres and major research networks. More than 177 million Euro in third-party funding were acquired by TU Berlin in 2015.

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About NIFDC

National Institutes for food and drug Control (NIFDC), founded in 1950, is a subordinate agency of the China Food and Drug Administration (CFDA) and there are more than 50 departments and divisions within NIFDC. The main professional areas of NIFDC cover pharmaceutical products, biological products, medical devices, food, healthy food, Cosmetic, reference standards, laboratory animals, and drug safety evaluation etc. More than 800 different testing items could be performed in NIFDC. Each year, more than 13,000 batches of drugs are tested in NIFDC and more than 2,900 reference standards are distributed by NIFDC. Currently, there are more than 1000 employees including 800 technical staffs and more than 9800 modern testing instruments and equipment in NIFDC, with the total asset value of more than 400 million RMB.

TissUse presents technologies at the WC9-congress in Prague

TissUse is a German, Berlin-based, vibrant growth company providing high-value services in the area of tissue culture analysis of drug candidates, cosmetics and chemicals. TissUse is presenting its new products and prototypes based on its proprietary technology platform at the “9th World Congress on Alternatives and Animal Use in the Life Sciences” from August 24 to 28 in Prague. This “human-on-a-chip” platform enables the testing of drugs or chemicals on a set of miniaturized human organs emulating the biology of the human organism at the smallest possible biological scale. In the future, it will be possible, for example, to significantly reduce the number of animals used in pharmaceutical research and to substitute current alternative methods to animal testing.

Dr. Uwe Marx, founder and CEO of TissUse GmbH, is going to address the current developments and applications of the technology during a keynote speech at the WC9-Congress. TissUse launched its two-organ-chip in 2013. The platform has been successfully applied in more than 20 different academic and industrial research projects. One of the globally renowned collaboration partner is Beiersdorf . Any new chip design serving specific customer needs in organ arrangement can be prototyped and produced within two months due to a proprietary rapid prototyping procedure established at TissUse. The technology offers a broad range of commercial and scientific applications.

“Design and development of new Chips are ongoing. Our latest research focus is based on the four-organ-chip prototype”, says Uwe Marx. This means that four independent organs on a chip interact on a physiological level. “The development of a ten-organ-chip is expected to be completed by 2017. Our approach could revolutionize drug development.” In addition to the keynote lecture, the technology platform will be prominently featured in a further presentation and seven posters. Visitors will have the opportunity to meet the development team at the TissUse exhibition booth or at the various posters. Furthermore, a four-organ-chip prototype will be exhibited at the booth.

About the technology

A dynamic two-organ-chip has been established for the simultaneous cultivation of two different cell types in a common media perfusion circuit at a miniaturized scale. Cells or tissues can be applied both into the two culture spaces on standard Transwell inserts to model biological barriers, such as intestine epithelia, or onto matrix supports to mimic the three-dimensional environment of parenchymal organs, such as the liver. The on-chip micropump and microfluidic channels interconnect these organs and provide lifelike behaviour. This enables the direct prediction of effects of chemicals and their metabolism on near real-life models.

Ownership of patent portfolio enables commercial production of multi-organ-chips

TissUse GmbH today announced the signing of a transfer agreement with the Technische Universität (TU) Berlin. With this, five patent families for the production, application and automation of multi-organ chips are fully transferred to TissUse GmbH, the TU Berlin spin-off company founded in 2010. The biotech company produces models of human organs for preclinical drug testing based on this patented technology. The patent transfer allows TissUse the unlimited full development of the multi-organ chips and their commercial application.

“We thank the TU Berlin for the constructive negotiations for the transfer of the patents,” said Dr. Uwe Marx, CEO of TissUse GmbH. “The collaboration with the TU Berlin has proven to be excellent for our young company and will continue.” The patents were developed within the framework of the Federal Ministry of Education and Research (BMBF) funded GO-Bio Project at the TU Berlin. TissUse has had access to the technology since 2010 through an option and license agreement with ipal Gesellschaft für Patentverwertung Berlin mbH (Association for Patent Exploitation).

The multi-organ chip technology makes it possible to carry out chemical and pharmaceutical tests on individual or related human mini organs (organoids). In this way, the validity of preclinical testing can be increased in the future compared to the current animal experimentation conducted, and the failure rate in clinical trials on humans in the pharmaceutical industry can be reduced. So far, about 20 academic and industrial research institutions have tested the two-organ chip, which is ready for production. Within two months, TissUse will be producing tailor-made two-organ models to fulfil the needs of specific research projects. The potential applications, however, range much further: “As a next step, we have embarked on the development of a four-organ chip,” commented Uwe Marx. “Our development has a bright future – especially with the full use of the patents within TissUse.”

TissUse has also, at the same time, received an exclusive license for a promising cell therapy to combat hair loss, which was developed by the same department of the TU Berlin. “We are carrying out first clinical testing of this therapy with hair transplant centres worldwide,” said Marx.