AG „GRADIERTE IMPLANTATE UND REGENERATIVE STRATEGIEN“ (Prof. A. Hoffmann)

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NIFE - Making-of

Partner

AG „GRADED IMPLANTS AND REGENERATIVE STRATEGIES“ (Prof. A. Hoffmann)

Management

Prof. Dr. rer. nat. Andrea Hoffmann

Employees

Kirsten Elger, MTLA

Anika Hamm, BTA

Yvonne Roger, PhD

Nina Friese: M. Sc. Biomedizin

Mattis Gierschner: M. Sc. Biochemie

Karolina Heinrichs: B. Sc. BIochemie

Dr. rer. nat. Patrik Schadzek

Graded implants and regenerative strategies in the skeletal system

Our group is located in the research department of the department of orthopaedic surgery: www.lbb-mhh.de. While the LBB (laboratory for biomechanics and biomaterials) is located on the campus of the Annastift our group is working in NIFE. Our scientific questions address molecular and cell biological aspects within the skeletal system (“musculo-skeletal system”: skeletal system plus muscles).

Bone, cartilage, muscles, tendons and ligaments and the joints of the musculo-skeletal system are built by a variety of cell types. Whereas bone is one of those tissues of our body with a high self-healing potential cartilage, tendons and ligaments have much less regenerative capacity due to their lack of supply with blood vessels and nerves. In conclusion, functional restoration of cartilage, tendons and bone is much more difficult. The investigation of molecular mechanisms which allow the generation of the different mature cell types within the musculo-skeletal system starting from mesenchymal stromal/stem cells (MSCs) therefore is an important focus of research. We hope that this will ultimately allow a better tissue restoration in patients. To sum up, the work in our group in mainly basic research. However, building on these activities, we are also developing translational approaches, e. g. to optimize medical implants or biomaterials. In this respect we also investigate inasmuch stem cells from bone marrow can be switched (“reprogrammed”) into cells with neuronal activities.

MSCs are one important group of adult stem cells, with hematopoietic stem cells being the most prominent representatives of adult stem cells. Apart from bone marrow MSCs are found in many more human tissues, e. g. in fat tissue, umbilical cord tissue, amnion or in dental tissues. This can be explained by the notion that probably, MSCs are derived from pericytes and adventitial cells (perivascular cells) which surround endothelial cells of blood vessels. The stem cell niche of MSCs therefore seems to reside in the perivascular space. In order to distinguish MSCs in vivo and their in vitro expanded counterparts the terminology MSCs = mesenchymal stem cell (in vivo) and BM-MSCs = bone marrow-derived mesenchymal stromal cell (in vitro, including designation of the tissue of origin) can be used, with the abbreviation MSCs being the common denominator. The ease with which MSCs can be isolated and expanded from different human tissues has in the past favoured to focus on cultivated cells. Elucidation of the in vivo identity and biology of the cells, on the contrary, was largely neglected. Since the present culture conditions are not able to appropriately mimick the stem cell niche of MSCs cultured cells are quite distinct from cells in vivo. In conclusion, MSCs may present the very group of adult stem cells which are still least defined and understood.

Properties of mesenchymal stromal/stem cells.

On the left the central in vitro cultured stem cell with its characteristic fibroblast (plastic adherent) morphology is depicted. In addition, these cells are characterized by a particular pattern of surface antigens (“immune phenotype”), the secretion of soluble factors (“paracrine effects”) and their differentiation (“differentiation”) into distinct mesenchymal cell lineages. For more information see text.

Research topics

Graded implants

In this research topic a concrete translation of results from our own basic research into a medical approach is followed with the DFG-funded research unit FOR 2180: Together with colleagues from the LUH and the Technical University Braunschweig we are working in NIFE on the development of a novel biodegradable and graded implant with the aim of restoring tendon-bone junctions in vivo. By identification of novel factors we aim to avoid cell-based therapies with the ultimate aim of optimized treatment for patients.

More information on this project is presented here: www.mh-hannover.de/9825.html and www.gradierte-implantate.de

Optimization of neuroprostheses

For further development of implantable neuroprostheses electrodes made from soft and biocompatible materials with optimal electrochemical properties have to be used. Aim of this DFG project which we perform in collaboration with the Laser Zentrum Hannover (Prof. B. Chichkov) and the institute of biophysics of LUH (Prof. A. Ngezahayo) therefore is to use polymers based on organic macromolecules for an enhancement of electrodes for neuroprostheses. This shall be achieved through three modules which incorporate novel approaches both from the material science and biological point of view: the preparation of electrochemically attractive polymers by use of metallic nanoparticles, surface microstructuring of these polymers, and the biological demonstration of neuronal activities in appropriate cell culture systems. For the in vitro cell studies the biological demonstration of neuronal activities and adequate cell adhesion will be performed with human MSCs since primary human nerve cells are hardly available. Mesenchymal stem cells respond to material properties and have an inherent potential for neuronal differentiation.

Regenerative strategies

Function of human MSCs

a) Maintenance of stem cell functions

b) Generation of cells of the musculo-skeletal system

under normal and inflammatory conditions (e. g. rheumatoid arthritis)
Development of optimized methods for isolation, cultivation and clinical use of MSCs

Using biochemical, molecular-biological and cell-biological methods we aim to enhance the understanding of basic principles of stem cell functions under normal and inflammatory conditions. The factors that we investigate contribute to either the maintenance and so-called potency of stem cells or control the differentiation of the stem cells into distinct cell types. This differentiation can be altered under inflammatory conditions. “Factors” in the narrower sense are genes or proteins like growth and transcription factors including Bone Morphogenetic Protein 2 (BMP2) or Smad8 L+MH2, cell-surface antigens or signaling mediator proteins like Transforming Growth Factor-Beta Activated Kinase 1 (TAK1) that guide cellular processes. “Factors” in the wider sense may also comprise native or genetically modified stem cells and other cells.

One aim is the long-term development of improved methods for cultivation and expansion of MSCs by the use of alternative materials, coatings, surface structuring or media additives in order to enhance their clinical applicability.

In cooperation with the department of rhino-oto-laryngology MSCs are modified with neurotrophic growth or transcription factors for use as a drug delivery device for cochlea implants or for a direct reprogramming into neuronal-like cells. Therefore the group is located within VIANNA (VerbundInstitut für AudioNeurotechnologie, NAnobiomaterialien und Lasermedizin, within NIFE): www.vianna.de.

Additional information

We offer the following methods for know-how transfer: Protein gels/ western blots, cloning, work with recombinant lentivirus and human MSCs, cell culture of MSCs and cell lines
We can offer the following apparatur for use: Film developing machine, shaker for bacterial cultures, cell-biological incubator with O2-regulation (for hypoxia)

Publikationen 2018

Jungwirth, N., Salinas Tejedor, L., Jin, W., Gudi, V., Skripuletz, T., Stein, V.M., Tipold, A., Hoffmann, A., Stangel, M., Baumgärtner, W., Hansmann, F. (2018): Mesenchymal Stem Cells Form 3D Clusters Following Intraventricular Transplantation. Journal of Molecular Neuroscience. 65:60 - 73

Quaas, B., Burmeister, L., Li, Z., Nimtz, M., Hoffmann, A., Rinas, U. (2018): Properties of dimeric, disulfide-linked rhBMP-2 recovered from E. coli derived inclusion bodies by mild extraction or chaotropic solubilisation and subsequent refolding. Process Biochemistry 67, 80 - 87

de Cassan, D., Sydow, S., Schmidt, N., Behrens, P., Roger, Y., Hoffmann, A., Hoheisel, A-L., Glasmacher, B., Hänsch, R., Menzel, H. (2018): Attachment of nanoparticulate drug-release systems on poly(ε-caprolactone) nanofibers via a graftpolymer as interlayer. Colloids and Surfaces B: Biointerfaces 163, 309 - 320

Weist, R., Floerkemeier, T., Roger, Y., Noack, S., Franke, A., Schwanke, K., Zweigerdt, R., Martin, U., Willbold, E.*, Hoffmann, A.* (2018): Differential expression of cholinergic system components in human induced pluripotent stem cells, bone marrow-derived multipotent stromal cells, and induced pluripotent stem cell-derived multipotent stromal cells. Stem Cells and Development 27, 166 - 183

Publikationen 2017

Schulze, J., Kaiser, O., Paasche, G., Lamm, H., Pich, A., Hoffmann, A., Lenarz, T., Warnecke, A. (2017): Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics. PLoS One, 12: e0178182

Rahim, M. I., Weizbauer, A., Evertz, F., Hoffmann, A., Rohde, M., Glasmacher, B., Windhagen, H., Gross, G., Seitz, J.-M., Müller, P. P. (2017): Differential magnesium implant corrosion coat formation and contribution to bone bonding. Journal of Biomedical Materials Research Part A 105, 697 - 709

Hoffmann, A., Floerkemeier, T., Melzer, C., Hass, R. (2017): Comparison of in vitro-cultivation of human mesenchymal stroma/stem cells derived from bone marrow and umbilical cord. Journal of Tissue Engineering and Regenerative Medicine 11(9):2565-2581 (Review)

Publikationen 2016

Schäck, L., Budde S., Lenarz T., Krettek C., Gross G., Windhagen H., Hoffmann A.*, Warnecke A.* (2016):

Induction of neuronal-like phenotype in human mesenchymal stem cells by overexpression of Neurogenin1 and treatment with neurotrophins.

Tissue and Cell; doi:10.1016/j.tice.2016.06.011

Roger, Y.,Schäck, L.M., Koroleva, A., Noack, S., Kurselis, K., Krettek, C., Chichkov, B., Lenarz, T., Warnecke, A.*, Hoffmann, A.* (2016):

Grid-like surface structures in thermoplastic polyurethane induce anti-inflammatory and anti-fibrotic processes in bone marrow-derived mesenchymal stem cells.

Colloids and Surfaces B: Biointerfaces; Vol. 148, p. 104 - 115

*: gleichwertiger Beitrag