Toxicology and Immunotoxicology


New strategies in the fight against the widespread disease periodontitis

Periodontitis is an inflammatory disease of the periodontium that can lead to destruction of tissue and bone around the teeth. The disease is caused by bacteria that settle in plaque and gum pockets and trigger an inflammatory response. If left untreated, this leads to damage to the entire periodontium and even tooth loss. Various studies also show a direct link between periodontitis and other diseases such as cardiovascular disease and diabetes, as well as an increased risk of stroke.

The basis of the novel treatment concept is the inhibition of an enzyme that occurs almost exclusively in the bacteria that cause periodontitis and regulates the production of various virulence factors there. By selectively inhibiting these factors, the pathogenic germs can be specifically suppressed and the natural microbiome preserved. The use of classical antibiotics, on the other hand, leads to growth inhibition of all oral germs, which carries the risk of rapid and stronger recolonization by the pathogens.

The aim of the project is to test appropriate drug candidates for their efficacy and safety, thus creating the prerequisite for a clinical trial for initial testing in humans. The collaborative partners will address various regulatory aspects, including resistance formation, material compatibility, toxicity and safety.

Within the framework of a GLP study, toxicity and safety are being investigated at Fraunhofer IZI both in vitro and in animal models.

The development and validation of bioanalytical methods for the comprehensive characterization of the drug candidates is carried out at the Fraunhofer IZI Department of Drug Design and Target Validation.

Development of a manufacturing platform for the generation of absorbable implants for the complete regeneration of tendons and ligaments through 3-D printing (Liga-Forte)

Due to an aging population as well as the generally increased exercise of many people, tendon and ligament injuries are among the most common injuries in Germany and worldwide, with high costs for the healthcare system. Surgical intervention is usually required, and after surgery there is a long recovery period during which movement, and thus the quality of life of patients is severely impaired.

Since tendons and ligaments have little regenerative potential, there are currently only few reconstruction options. They are limited to autografting and the use of non-absorbable fixation materials. However, autografting, the transfer of part of the ligament from a healthy site to the defect site, can lead to complications at the donor site. The use of non-absorbable materials, on the other hand, often leads to infections in the long term.

The project, "Development of an additive manufacturing platform for the generation of absorbable scaffolds using 3-D printing in combination with platelet-rich plasma for tendon/ligament reconstruction (Liga-Forte)," aims to use knowledge in the field of regenerative medicine to develop a better therapy for reconstructing such injuries. The project team plans to develop the world's first absorbable implant for the complete regeneration of tendons and ligaments. For this purpose, the scaffolds (implants) will be mixed intraoperatively with autologous platelet-rich plasma to enable the regeneration of native tissue. In parallel, a manufacturing process will be established that will enable the production of non-planar ligament scaffolds. Furthermore, the project partners intend to develop surgical techniques to fix the scaffolds and perform a biomechanical evaluation of the same on different tendons and ligaments of the sheep’s hind leg.

The project, funded by the Sächsische Aufbaubank, is led by BellaSeno GmbH. At Fraunhofer IZI, the first basic efficacy study will be performed in the sheep model to evaluate the feasibility of this new regenerative approach.

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NANOpain – Preclinical models to evaluate the safety of a nanoparticle-conjugated opioid

As part of a joint project funded by the BMBF, a combined drug product for pain relief is being investigated in preclinical studies. The aim is to minimize safety risks prior to first-time use in patients. The NANOpain project is based on a combination of an already approved opioid (preferably kappa-receptor agonist) and a dendritic nanotransport molecule (nanocarrier). According to the EPR effect (”enhanced permeability and retention effect”), the dendritic molecules preferentially accumulate in inflamed and tumorous tissue resulting in a targeted localization and a reduction of side effects such as addiction, aversion and constipation. The efficacy has already been tested by DendroPharm both in vitro and in vivo. At Fraunhofer IZI, the safety-relevant preclinical investigations are carried out in appropriate animal models (small animal model, large animal model) under GLP conditions. First, a pharmacodynamics / pharmacokinetics study is performed in rats to investigate the degradation of the drug as a function of time. The analyses are performed by the GLP testing facility at the Halle site. The toxicological tests of the active ingredient preparation are then implemented in a mouse model as well as in a minipig model. Together with the production of the investigational drug under GMP conditions by DendroPharm, this creates the prerequisite for subsequently testing the developed drug in a Phase I clinical trial at the Fraunhofer Institute for Toxicology and Experimental Medicine. The drug will be tested for safety and tolerability in healthy volunteers in ascending single and multiple doses.

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

As part of a project funded by the Sächsische Aufbaubank (Saxon Development Bank, SAB), preclinical safety tests will be conducted in the NSG mouse as a small animal model in order to verify the safety of a cell transplant for treating cartilage defects. The tests will specifically look at mesenchymal stromal cells taken from umbilical cord tissue that were expanded in a GMP process in combination with a collagen matrix. The safety tests include investigations into biodistribution by means of PCR analyses and also into tumorigenicity by drawing on immunohistological methods.

The project will pave the way for subsequent authorization in Germany and for further clinical trials involving this form of cell therapy.

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

GLP study to assess the systemic toxicity and immunotoxicity of a therapeutic HBV vaccine (TherVacB)

In two preclinical study arms, both the systemic toxicity of therapeutic vaccines and immunotoxicity are being assessed in the relevant disease model in mice. This will enable potential, toxic side effects of the individual vaccine components (HBV peptides, adjuvants, MVA vector) to be examined at a repeated maximum dose in a predetermined vaccination schedule with the aid of histopathological, hematological and clinical-chemical analyses. A relevant murine disease model that imitates the condition of chronic hepatitis will be used with the aim of assessing immunotoxic effects on the one hand and confirming the efficacy of the vaccine on the other.

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
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 Department of GMP Cell and Gene Therapy. 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 management
Dr. Jörg Lehmann

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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