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Employing Mechano-Biology and Shaping Inflammation to Enhance Endogenous Regeneration

Both mechanical and biological processes work together to determine the outcome of musculoskeletal regeneration. Whilst many of the biological factors have been identified and some even brought into clinical practice (BMP's, PDGF, IGF, etc.), the impact of the mechanical environment and the role of the immune system are only recently taken into account. In contrast, the possibility to modulate cellular processes by creating specific environments seems to be a promising strategy to guide tissue formation along endogenous healing cascades towards successful regeneration.

Following Junior Reseach Groups (JRG) are assigned to the work area.

  • JRG "Development of Intra-Operative Cell Therapies" (Dr. Anke Dienelt: BCRT, Charité)
  • JRG "Cellular Biomechanics" (Dr. Ansgar Petersen: BCRT, JWI, Charité)
  • JRG "Controlled Tissue Formation" (Dr. Evi Lippens: BCRT, JWI, Charité)
  • JRG "Physical Cues and Regeneration" (Dr. Amaia Cipitria: BCRT, JWI, Charité)
  • JRG "Prognostic Markers and Targeted Therapy" (Dr. Sven Geißler: BCRT, JWI, Charité)

Research Focus

We aim at a deeper understanding of cellular processes and the role of the cellular environment and at identifying tools to modulate the regeneration process. Such a modulation can, for example, be created by biomaterials that provide specific mechanical signals to the cells (e.g. via mechanical properties like substrate stiffness, surface topography, and pore architecture) and that posses specific resorption kinetics. From an analysis of cellular responses to the variation of such parameters, materials can be developed that provide environments that foster specific cell functions like migration, differentiation and formation of extracellular matrix (Figure 1 and 2). Those environments might be spatially and temporally distinct to account for the need in different healing cascades. The necessary knowledge is gained from in vivo investigations using 3D biomaterials in tissue defect models (e.g. in bone and muscle) in combination with the cultivation of primary cells inside biomaterials using bioreactor systems that mimic the in vivo situation. By the combination of both, endogenous processes can be understood and eventually modulated via the control of the mechanical environment. Besides the use of biomaterials to guide tissue formation, the understanding and the modulation of the immune response during regeneration is a further focus of our research. The tight interaction of the immune and skeletal system is visible in common precursors and shared signaling molecules of these cells which both reside in the bone marrow. Studying the role of immune cells during bone healing and the impact of the absence of the adaptive immune system on the outcome of bone regeneration revealed the importance of specific immune cell subsets for fracture healing (Figure 3). Identifying immune cell subsets with positive or negative effects on the regenerative healing process of bone enables the development of therapeutic approaches needed in a population with a growing percentage of ages and therefore immune compromised patients with a high fracture risk.

Methods

  • Small animal (mouse, rat): fracture-, osteotomy-, defect-models in long bones
  • Large animal (sheep): osteotomy- and defect-models in long bones
  • Biomechanical characterization
  • In vitro cultivation under in vivo-like conditions using bioreactors
  • 3D proliferation, migration and differentiation assays for primary cells in biomaterials (fibroblasts, mesenchymal stromal cells, osteoblasts)
  • Histology and histomorphometry
  • Confocal and multiphoton imaging, time lapse microscopy (tissue and cell characterization)
  • Immunohistochemistry and in situ hybridization
  • FACS analysis, mRNA and protein quantification

Team

Cooperations