Ongoing Project

that maintain the tissue’s mechano-biological requirements. The common focus of the TOM group is to advance in vitro organ culture models, which match closely the human situation and where regenerative therapy strategies, such as novel biomaterials and cells, can be tested in a most authentic in-vitro set-up.

Translational Research due to active collaborations at the Insel Hospital

The Gantenbein group established long-term collaborative projects with orthopedic surgeons from the University Hospital, namely with the Spine Unit, led by PD Dr. Christoph Albers and PD Dr. Moritz Deml. The team of Prof. Gantenbein contributes with core competence in “fishing” a rare stem cell population of the intervertebral disc using patient-derived primary cells from the Insel Hospital. Further collaborations are ongoing with other members of the Spine Unit, i.e., with Prof. Dr. Dr. Frank Klenke (leader Knee Team) and PD Dr Michael Schär (head of the shoulder team). the exploration of BMP analogues for improved spinal fusion in a rat tail animal model This work is currently ongoing using a rat tail spinal non-union model. Also, bone biology projects are in progress on the role of BMP inhibitors on osteoclast biology and contrast-agents on bone turnover (co-supervised by Prof. Willy Hofstetter). Furthermore, close collaborations with Prof. Dr. Benoît Schaller and with PD Dr. Nikola Saulacic from the Department of Cranio-Maxillofacial Surgery are ongoing.

Mechano-Biology

In terms of mechano-biological oriented research the group developed a customized two Degree-of-Freedom bioreactor to culture intervertebral disc organ explants under compression and torsion. This device attracted other research groups all over Switzerland for collaborations and also gained high reputation internationally. The customized device allows the pre-clinical testing of regenerative approaches with cells and biomaterials (currently silk scaffolds) to the IVD under a physiological set-up. It should be highlighted that the two research groups are in demand of a proximity to the animal facility and also to clinicians that provide clinical support for the cluster’s research. 

Most recently, four key topics were established in the laboratory on intervertebral disc (IVD) research.

1. Tissue-specific stem cell research for the intervertebral disc
2. Silk engineering for intervertebral disc repair
3. To mimic and understand causality for causes for intervertebral disc degeneration using 3D-oranoid-like culture systems
4. To impove spinal fusion using ceramics and BMP2 and the BMP2 analogues coating.

The first topic is on the isolation and culture of specific progenitor cells that were recently characterized by Prof. Daisuke Sakai, an orthopaedic surgeon from Japan, who initiated this research. This progenitor cell research is financed by iPspine, a 16 M € research project, which was funded to the consortiums leader Prof. Marianna Tryfonidou, a leading veterinarian from the University Medical Center (UMC) Utrecht & Universiteit Utrecht (https://cordis.europa.eu/project/id/825925). The iPSpine partners, which include both universities and companies, joined together in January 2019 to begin researching a new, advanced therapy for the treatment of LBP caused by disc deterioration. The ultimate aim of this project is to investigate and develop a new advanced biological therapy using a type of cell called induced pluripotent stem cells (iPSCs) (https://ipspine.eu). These cells are created by re-programming fully mature cells, such as cells from blood or skin, into spine-specific cells. These iPSCs are then differentiated into disc cells that can repopulate the group of original cells that have degenerated. Over the next five years, the iPSpine partners want to show that iPSCs can work as a therapeutic strategy. This will start with basic laboratory research to create the cells and will continue on into a preclinical animal model. By the end of the project, the therapy should be ready for advancement to the first clinical trial in people.  

Within this highly cross-disciplinary consortium our group was able to isolate primary cells isolated from human trauma IVDs with written consent from patients. These cells were then isolated from the primary tissue, cell sorted using a cell surface marker and delivered to consortium partners at the INSERM in Montpellier and Nantes, France. These partners at INSERM were then able to derive novel iPS cell lines from these primary cells. These cell lines will provide valuable information to future generation researchers and whether these can be used for future cell therapy to possibly cure degenerated IVDs.

A second highlight is the investigation into engineered silk scaffolds for IVD repair. Previous research by the TOM group investigated on the usage of silk for the production of a scaffold for IVD repair, which would recruit or activate existing cells of the degenerated disc or novel cells would be seeded de novo. Here, a new project funded by the Swiss National Science has just been started that targets regeneration of the IVD by using “cross-linked growth-factors and engineered” silk fibres and using knitting techniques developed by Dr. Michael Wöltje at the “Technische Universität Dresden, Institut für Textilmaschinen und Textile Hochleistungswerktofftechnik”, Dresden, Germany.

Another topic of interest in the group addresses the bone healing process in osteoporotic bone that is under treatment with bisphosphonates (BP). Previously, the group demonstrated that BP affect healing of an osteotomy, inducing an exuberant bone formation and an impairment in the turnover of the mineralized cartilaginous callus forming after non-rigid defect fixation (Hauser M). Since large bone defects frequently require the use of biomaterials as bone fillers and since we have previously shown that efficient bone formation in critical size defects is paralleled by a turnover of the biomaterials (Sebald HJ, Hauser M) we investigate the healing process of critical size defects in a murine model of osteoporosis and treatment with BP. To obtain in detail mechanistic insights into the processes, transcriptome analysis will be performed and will be compared to histological analysis. A major focus will be placed on the coupling of material turnover and bone formation since the first takes place only, when the second is being enabled.

Osteoimmunology is a topic that combines many areas of musculoskeletal diseases, i.e. Rheumatology, Osteoporosis, systemic inflammatory diseases. We have shown in many instances that immunological mediators in health and disease affect bone metabolism (Balga R, Atanga E, Gengenbacher M, Balani D). In collaboration with PD P. Krebs, Institute of Pathology, we presently investigate a mouse model deficient in a SH2 domain-containing inositol-5-phosphatase 1, a negative regulator of PI3K/Akt signal pathways expressed in haematopoietic cells. Previously, we found a reduced bone mass in these animals. It was, however, not clear, whether this phenotype was due to an increase in bone resorption or an impairment of bone formation. Studies elucidating these points are currently under way, combining in vivo, cell biology and molecular approaches.

In a collaborative effort with the Clinics of Radiology (PD R. Egli) we investigate the role of Gadolinium (Gd) in bone biology. Gd containing contrast agents are widely used in Radiology, and it is a well-established observation that Gd accumulates in cells of the CNS and in bone. Long term effects, however, have not yet been elucidated and it is the aim of this project to assess Gd effects on bone. In a first step, the effects of Gd, either as salt or in complexed forms on the development and activity of bone cell lineages will be investigated before suitable in vivo models will be set up.