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.

Figure 1: In vitro studies of cell-material interaction: A Bioreactor system for enhanced cell culture in 3D materials provides the possibility for mechanical stimulation and characterization; B Example of a scaffold with a specific pore architecture to guide cell behavior (Optimaix, Matricel GmbH). The high pore orientation leads to the formation of oriented extracellular matrix (ECM) components like collagen C and fibronectin D (scaffold pore walls highlighted by white dashed lines); E Pore architecture is also able to guide cell migration into a preferential direction, indicated by the arrow; F Alterations of pore geometry can be used to modulate cell organization, ECM structure (circular in F rather that linear in C,D) and dynamics of tissue growth (fibronectin in red, actin cytoskeleton in green). Scale bar is 100µm, same scaling in pictures B, C, E.


To top

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

To top

Team

Group Picture AG Duda
(LTR, first row) Grit Nebrich, Kristin Strohschein, Nicole Bormann, Amaia Cipitria, Gabriela Korus, Iwona Cichocka, (second row), Georg Duda, Liliya Schumann, Dorit Jacobi, Simon Reinke, Sven Geißler, Anke Dienelt, Ansgar Petersen, (last row) Martin Textor, Janosch Schoon, Andrea Sass, Frank Schulze

To top

Cooperations

To top

Contact

Charité - Universitätsmedizin Berlin
Berlin-Brandenburg Center for
Regenerative Therapies
Campus Virchow-Klinikum
Julius Wolff Institute &
Center for Musculoskeletal Surgery
Augustenburger Platz 1
13353 Berlin
Germany

Phone: +49 (0)30 450 559 079
Fax: +49 (0)30 450 559 969
Email: georg.duda@charite.de

To top