Translational center "Regenerative therapies", Würzburg branch

The Translational center "Regenerative therapies for Oncology and Musculoskeletal Diseases" performs in close collaboration with the Institute for Tissue Engineering and Regenerative Medicine at the University Hospital Würzburg methods and procedures to develop therapeutics for cancer. These therapeutics are placed along the value chain in an interdisciplinary and international team – as a Würzburg Fraunhofer interface between health research and medicine engineering – applying human vascularized 3D (tumor) tissue models in preclinical and clinical studies.

Fields of research

In Germany, 450,000 people suffer and 216,000 people die from cancer each year. After cardiovascular diseases, cancer is the second leading cause of death. Cancer cells grow uncontrollably and form their own nutrient-supplying blood vessels. Many tumor cells move through the blood or lymphatic system to distant organs and form metastases, which often lead to incurable cancer. An important goal of our work is to therefore discover the mechanisms of cancer growth, metastasis, and their distribution in the human body.

The scientific focus of our research is on the development of human 3D tissue equivalents on an acelluarized, vascularized intestinal matrix BioVaSc. By applying tissue engineering methods, we produce human 3D tumor tissue on the BioVaSc in combination with primary tumor cells and various tumor cell lines to get the mechanisms of novel therapy strategies in a complex human pathological environment examined.

The Translational center succeeded in establishing various tumor models in different complexities such as lung tumor models or models for colorectal carcinoma, for breast cancer, leukemia and for malign peripheral nerve sheath tumors (MPNST). Beyond the standard divisional rate and apoptosis of tumor cells, various molecular activations and inhibitions of signal cascades can now be measured after a treatment with agents. Based on these data, “in silico”-models are created, refined, and validated in cooperation with the Department of Bioinformatics of the University Hospital Würzburg. The co-culture with cells from the tumor stroma additionally allows the examination of the reciprocity of agents, among them biologicals such as anti-bodies, with stromal and with tumor cells of their surroundings and to further examine the formation of resistance or metastases. In the future, we want to refine characteristics of metastasizing tumor stem cells.

The application of 2D monolayer cultures and cell lines is limited when clarifying certain regenerative mechanisms, the examination of physiological barrier functions, and the resorption processes in humans. Based on the BioVaSc, we developed complex tissue models of the human barriers skin, cornea, bowel, trachea, lung, and the blood-brain-barrier. We adapt these tissues to diseases (disease-models) or we simulate infections of germs and, accordingly, we establish long-time cultures. Equally, we simulate reciprocal effects of medical products such as stents to optimize the surface of the implants. In the EU project IDEA, we use vascularized tissue models to develop diagnostics (nanoparticles) and to test their safety. In the EU projects Bio-Inspire and VascuBone, we are developing stem cell-based musculoskeletal therapies; the necessary preclinical studies are in progress with international partners from Norway, Austria, and Australia. Clinical studies of these novel innovative ATMPs (Advanced Therapies Medicinal Products) are prepared in Germany, Austria, and Norway. The culture of our vascularized matrix (BioVaSc) in specific bioreactors where we can also generate complex vascularized implants has now also been established under GMP conditions in cooperation with the University Hospital Würzburg. In the framework of a BMBF-funded project, we are preparing first clinical studies for a trachea transplant based on the BioVaSc.

Our research services can be used for the entire value-added chain in the development of cancer therapies.

Good to know

  • How does a tumor evolve?

Strictly spoken, cancer is a side-product of evolution: mutations are generated during the replication of DNA and – on the one hand – can improve the organism’s fitness but – on the other hand – can promote cancer if the mutations affect proteins which are involved in cell cycle regulation. Most mutations don’t have any effects for the organism or are eliminated by specific repair mechanisms. However, an increasing number of mutations (e.g. induced by radiation or carcinogenic chemicals) can lead to an enhanced risk of developing one cancer cell which produces a tumor one day. Tumor cells are immortal cells and proliferate into more and more tumor cells. The surrounding tissue supports this proliferation as well as the survival of these cells because cells of this surrounding tissue are induced by the tumor cells to secrete growth factors. Among others these cells secrete angiogenic substances which induce the formation of new blood vessels to supply the growing tumor. A tissue which contains vessels is described as being vascularized.

Projects

The Translational center works closely with the Department of Tissue Engineering and Regenerative Medicine in Würzburg.

Development of an intestine tumor model

By using of human adenocarcinoma cell lines we want to build up three-dimensional in-vitro tumor models based on the BioVaSc®. These models are going to be used for testing of new cancer therapies.

 

Investigation of stroma-tumor interactions

Tumor-associated fibroblasts play an important role in tumor progression and are a possible target for cancer therapies. They are part of the connective tissue (stroma) which subdivides the organs of the body. In a tumor, all non-tumorous cells are called stromal cells, most of them are fibroblasts. As result of an injury such as a lesion fibroblasts become temporarily activated and induce proliferation of organ tissue cells which leads to wound healing. In a tumor, the fibroblasts become permanently activated and are involved in tumor progression. For this reason, cancer is often described as “wounds that do not heal” (Dvorak HF., Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650–9.)

 

Development of a lung tumor model

Comparable to the generation of a colon cancer model we want to establish a human in-vitro tumor model of lung adenocarcinoma by using the BioVaSc® technology. This model is going to be used for substance testing and for the investigation of tumor-stroma interactions.

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  • Combined in-silico/in-vitro lung model
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    Neurofibroma model

    In cooperation with the Charité Berlin, we use cell cultures derived from Neurofibromatosis (NF)-1-associated tumors (e.g. Neurofibroma) as well as primary cells derived from healthy skin biopsies (endothelial cells, fibroblasts) to generate a three-dimensional in-vitro tumor model based on the BioVaSc® to investigate the very complex disease neurofibromatosis. We focus on the analysis of the development of malignant peripheral nerve sheath tumors (MPNSTs) which derive from originally benign tumors. Moreover, tumor-stroma interactions are going to be analyzed in this project.

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    Cornea model test system

    Chemicals, cosmetics and pharmaceutical products must be tested and classified. Currently, the tolerability and irritation potential of substances that come in contact with the eyes are performed with the "Draize test", where the test substance is added to the lid sack of a rabbit eye and the chemical injury is observed for several days or weeks. Culturing the cornea near in vivo conditions with a specialized bioreactor, Fraunhofer IGB has developed a cornea-based test system. Using the bioreactor, we can even mimic the natural moistening blink of the eye. Our cornea organ model-test system allows the testing of substances making experiments on living animals unneeded while performing with an equivalent or even significantly stronger power.

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Range of services

  • Production and biochemical modification of tissue-engineered electrospun 3D scaffolds
  • Isolation of primary human stem and tumor cells
  • Establishment of co-cultures for the generation of human solid tumors in vitro and tumor test systems
  • Development of specific bioreactors for various tumor models
  • Development of human vascularized tumor tissue for the establishment of individual diagnostics and personalized therapies
  • Biological cell analysis of tumor tissue: molecular-biological, histological and immunohistochemical methods, flow cytometry (FACS), including sorting
  • Target screening for new cancer therapeutics

Our research services can be used for the entire value-added chain in the development of cancer therapies:

  • Investigation of the active principle and/or the side effects of new drug candidates utilizing vascularized human tumor test systems
  • Use of the tumor model in the process development of optimizing drugs or diagnostics
  • Implementation and validation of in vitro tests as alternatives to animal testing at the end of the preclinical development phase
  • Efficacy experiments of new drugs that are currently undergoing evaluation for clinical use
  • Cooperation with the medical faculty of Würzburg for the organization of the clinical phases I-III

Infrastructure and technical equipment

  • Cell culture laboratories for work on safety levels S1, S2 GenTSV
  • Cell analysis: Fluorescence microscope, FACS, microdissection system, Raman spectroscopy

Publications

  • Poster: Development and validation of a preclinical in-vitro tumor test system. Nietzer SL, Dandekar G, Walles H. Forum Life Science 2011, München.