Preclinical Models



Preclinical trials are underway to investigate a combination painkiller as part of a joint project funded by the German Federal Ministry of Education and Research. The project aims to minimize safety risks before the drug is used for the first time in patients. The preparation combines an opiate with a dendritic nanotransport molecule (nanocarrier). Preclinical investigations are being carried out under GLP conditions into the safety of the drug using appropriate animal models (small animal model, large animal model) at Fraunhofer IZI. Together with the investigational drug’s manufacture under GMP conditions by the company DendroPharm, the prerequisites are met for the developed drug to then be investigated in a phase I clinical trial at the Fraunhofer Institute for Toxicology and Experimental Medicine. The safety and tolerability of the drug will also be tested on healthy human subjects in single and multiple ascending doses. This marks a further step towards the market maturity of a potential, new pain medication.

Development of a novel therapeutic concept for chronic inflammatory bowel diseases (IBD) via non-toxic ligands of the aryl hydrocarbon receptor

The umbrella term chronic inflammatory bowel disease (IBD) covers disease patterns that are characterized by recurring or continuously emerging inflammatory changes to the bowels. The two main types of IBD are Crohn's disease and ulcerative colitis. In Germany, around 300,000 people currently suffer from these two disorders, which are associated with long-term abdominal pain and diarrhea as well as high levels of fatigue.

Conventional IBD therapies focus on repressing the inflammation using anti-inflammatory drugs. A cure is yet to be found for these diseases, which means any drug therapy generally has to be administered for a person’s entire lifetime. This is first and foremost due to the fact that these therapies are systemic treatments. A therapeutic approach is yet to be found which has a causal and sustainable impact on the dysregulation of the intestinal immune system associated with IBD. Surgical measures often give rise to complications and impact on quality of life. The gut microbiome, which is significantly influenced not only by nutrition but also by the use of antibiotics, plays an important role in the emergence of IBD. This is why nutrition and alternatives to antibiotics are playing an increasing role in the development of new approaches to treating these diseases. More recent studies attest to the fact that the aryl hydrocarbon receptor (AhR) presents a highly promising, novel therapeutic target in the case of IBD.

Furthermore, numerous research papers have shown that the AhR plays a significant role in both the innate and the adaptive immune system in terms of maintaining immune homeostasis and controlling inflammatory responses in the intestines. The AhR is central to the communication between immune cells and enterocytes. AhR ligands found in food or the microbiota activate the AhR, promoting the survival and proliferation of immune cells and making a substantial contribution to immune homeostasis. Based on the recently published AhR structure, a highly diagnostic pharmacophore model is to be developed which will be used to select new, previously unknown AhR ligands as candidates for future therapeutic application in IBD cases using structure- and ligand-based methods. Moreover, a drug repositioning approach is to be taken, i.e. drugs which have already been approved or drug candidates currently undergoing clinical testing are to be identified as potential AhR ligands for other indications.

This work was supported by the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD.


Project manager
Dr. Jörg Lehmann

GLP-compliant testing of an allogeneic, matrix-associated cell transplant comprising mesenchymal stromal cells taken from umbilical cord tissue

Articular cartilage injuries tend to go hand in hand with signs of progressive wear and tear. This results in arthrotic changes, pain and the loss of functionality in the joint. As articular cartilage has only limited regeneration potential, this process is often irreversible. With an eye to replacing cellular cartilage, mesenchymal stromal cells taken from umbilical cord tissue appear to present an attractive alternative source for regenerative therapies. The cells are young, vital and boast a high potential for proliferation and differentiation. They also have an immunomodulatory and anti-inflammatory effect. For allogeneic applications, there are additional benefits in terms of tolerance, extraction and ethical aspects.

The safety of this type of cellular therapy is to be verified at Fraunhofer IZI using a suitable small animal model. To this end, both the migration of the cells into other tissues and any tendency for the cells to form tumors are to be investigated. These preclinical tests are intended to evaluate whether the cell transplant complies with the legal safety requirements for such therapies.

This project is co-financed by tax revenues on the basis of the budget approved by members of the Saxon state parliament.

BioBreast – preclinical safety trials for a new type of breast implant

Testing a miniaturized version of the breast implant with an in vitro cytotoxicity assay
Testing a miniaturized version of the breast implant with an in vitro cytotoxicity assay.
Microscopic view of the cells under the scaffold structure of the implant
Microscopic view of the cells under the scaffold structure of the implant.

Breast cancer is the most common form of cancer among women around the globe, with therapy often involving the surgical removal of breast tissue. Following this kind of mastectomy, there are only a few options for reconstructing the breast. And these are not without their complications. The company BellaSeno GmbH has come up with an innovative solution strategy that presents an alternative to traditional implant products, e.g. silicone, to reconstruct the breast. By implanting a patient-specific scaffold structure made of bioresorbable polycaprolactone that is then filled with the patient‘s own body fat, the company’s approach to reconstruction would entail fewer complications. The final development stage of the implant as well as its manufacture and safety testing for approval as a medical device will be supported as part of an SAB project involving BellaSeno GmbH, GeSIM GmbH and Fraunhofer IZI.

Once BellaSeno GmbH has completed the final development stage, the scaffold structure will be manufactured using a 3D printing method under GMP conditions in the Main Department of GMP Cell and Gene Therapy (see page 23). The implantation strategy and the functionality of the implant will then be evaluated in the large animal model. As the new implant is a risk class III medical device, preclinical and clinical trials have to be carried out in accordance with the German Medical Devices Act in order to ensure biological safety in patients. The preclinical safety trials will be conducted in Fraunhofer IZI’s GLP test facility based on DIN EN ISO 10993. The trials characterize and analyze the degradation products used in the resorbable scaffold structure and also test for any potential cytotoxicity in vitro and systemic toxicity in the mouse model. Degradation studies have already been conducted in order to characterize the implant in greater detail; these studies identified the individual degradation products that make up the resorbable implant. Furthermore, the cytotoxic potential of the scaffold structure is currently being investigated in vitro under DIN EN ISO 10993-5. This will be followed by tests on local effects following implantation as well as on systemic toxicity in the mouse.

The aim of the project is to build the foundations for approving an alternative kind of implant to improve the regeneration of breast tissue with few complications. The longer term goal is for the implant to be approved as a medical device and tested as part of a clinical trial.


Project manager
Dr. Jörg Lehmann

This project is co-financed by tax revenues on the basis of the budget approved by members of the Saxon state parliament.

Plant extracts as active agents for the treatment of chronic inflammatory bowel diseases

Inflammatory bowel diseases (IBD), such as Crohn’s disease and Ulcerative Colitis, are multifactorial disorders of the gastrointestinal tract. The incidence and prevalence of these diseases have been rising constantly in industrial and newly industrialized countries for several decades. Although the diseases show a low mortality rate, patients suffer lifelong from episodes of severe pain and bloody diarrhea. The etiology of IBD is unknown but is assumed to be a combination of genetic predisposition, environmental factors and a dysregulated immune response to the gut microbiota. Hence, current therapies mainly focus on inhibiting the chronic immune response in the gut using immunosuppressive drugs and biologics. Since these therapies are often associated with strong side effects, pharmaceutical companies are pursuing the development of new IBD therapies with less side effects. The model often used for such developments - the acute dextran sulfate sodium (DSS)-induced colitis - cannot adequately represent the chronic course of the diseases. Therefore, the Preclinical Models Unit has developed a chronic model that better represents the course of disease and reduces animal burden. Due to its high reproducibility, the model is very well suited for the preclinical evaluation of therapeutic agents. The model of chronic DSS colitis has already been successfully applied in several industrial projects. Moreover, the therapeutic effect of a plant extract based on sage and bitter apple could be demonstrated in the frame of an internal research project. As a next step, the active components of the extract will be identified and tested for their therapeutic efficacy. The use of phytopharmaceuticals could result in a reduction of the dosis and hence the side effects of classical therapeutics. Furthermore, such therapies could be used in phases of remission and thereby prevent the development of resistance to classical therapeutics. The goal is to make the lifelong therapy needed by IBD patients as effective and tolerable as possible and thus improve the quality of life for these patients.


Project manager
Dr. Nadine Vollack-Hesse


Development and production of human monoclonal antibodies in a humanized mouse model

This project focuses on developing and producing new kinds of fully humanized monoclonal antibodies for the treatment of tumour diseases (pilot project: triple-negative breast cancer). The development and production of such antibodies can be divided into several steps: The first step entails establishing a humanized mouse model which can be used to generate human monoclonal antibodies against known and yet unknown tumour antigens. A variety of immunization strategies have been created for this purpose in immune-deficient NSG or BRGS mice, which have developed a humanized immune system after the transfusion of human haematopoietic stem cells from cord blood. Tumour-specific human monoclonal antibodies are generated by fusing tumour-specific human B cells from these humanized mice with human plasmocytoma cells, and selected using suitable strategies. Selected candidates are finally tested in an established tumour mouse model in preclinical studies and modified if required (e.g. antibody-drug conjugates), in order to continue improving therapeutic efficacy.

Project manager 
Claudia Müller


Preclinical animal models for the development of new IBD therapies

Inflammatory bowel diseases (IBDs) are multifactorial diseases of the gastrointestinal tract, the incidence and prevalence of which have been rising constantly in industrial and newly industrialized countries. The etiology of IBD is unknown but is thought to be a combination of genetic predisposition, environmental factors and a dysregulated immune response to the gut microbiota. Current therapeutic approaches, such as immunosuppressives and biologics, often show severe side effects. Thus, there is an urgent need for the development of new therapies based on improved knowledge of the etiological factors of IBDs.

The goal of the in-house research project is to develop and characterize different IBD animal models for testing new therapies and elucidating mechanisms of pathogenesis. Thus, a model of chronic DSS colitis was established which shows typical symptoms such as weight loss and chronic bloody diarrhea. Moreover, the colon tissue of the animals features a continuous immune reaction with resulting ulcerations. In addition, the bacteria-induced chronic colitis has been established as an alternative animal model for IBDs which mainly focuses on the role of the microbiota in disease pathogenesis and / or as a target for novel treatment strategies. Both models can be used for preclinical studies as well as elucidating IBD pathogenesis and developing new therapies. In the latter case, the focus is currently on evaluating the therapeutic potential of phytochemicals.

We are also performing a functional analysis of the gut microbiota in the chronic DSS colitis model using BALB/c mice, together with the Helmholtz Centre for Environmental Research UFZ. The goal of this project is to better understand the interactions of the microbiota and the mucosal immune system in IBDs.

Project manager
Dr. Nadine Vollack-Hesse

Immunomodulatory role of the arylhydrocarbon receptor (AhR)

Within the frame of this project, the immunomodulatory effect of the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) was characterized in collaboration with the Federal Institute for Risk Assessment (BfR). While the carcinogenic effect of BaP has been known for decades, little attention has been paid so far to the immunomodulatory effect of BaP, particularly of concentrations classified as uncritical. The immunomodulatory effects as well as the decomposition of BaP are mainly regulated by its binding to the arylhydrocarbon receptor (AhR) with subsequent receptor activation. A murine salmonella infection model is used to investigate the impact of BaP on an ongoing immune response. The analysis of the underlying mechanisms is carried out using suitable in-vitro models. Previous investigations have mainly been restricted to the maturation and functional activation of murine macrophages. By using AhR-deficient mice or cells from these animals, the AhR dependence of the observed effects  could be demonstrated. Interestingly, the initial findings in our model showed an AhR-dependent immunomodulatory effect of BaP which had a positive impact on the course of disease. In further experiments, selected non-toxic AhR ligands are being analyzed for their therapeutic potential in different disease models.

Project manager
Sina Riemschneider 

Completed projects

  • Study of the therapeutic efficacy of a transglutaminase inhibitor in an acute DSS colitis model
  • Study of the therapeutic efficacy of an ion-based immunomodulator in a chronic DSS colitis model
  • Development of a small animal model and in-vivo studies for evaluating the vitality of human cryopreserved adipose tissue transplants using modern imaging techniques
  • Analyzing the mechanisms of action and identifying clinically relevant effects of colocynth and sage-based phytopharmaceuticals