Macrophage plasticity deployed for efficient bone (re-) generation

• Applicant: Professor Dr. Lorenz Meinel
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 270576131

Macrophages (MPhi) achieve different activation states in response to environmental priming, the M1 ("classical" state involved in anti-microbial function) or M2 ("alternative" state involved in tissue repair). The potential to control MPhi skewing in an experimental system in vitro and in vivo by integrated bioresponsive drug delivery systems will open exciting new avenues to deploy the advantageous roles that M2-MPhi play in skeletal tissue formation - and more importantly angiogenesis - leading to superior host-implant integration in critical size bone defects. As a prerequisite to this endeavor, we will develop an experimental system composed of a column-like index compartment containing a three-dimensional bone-like tissue, engineered from human mesenchymal stem cells (hMSCs; TE-bone) which is inserted into a tube-like supply compartment within which M2-MPhi will be harbored. M2-MPhi status is controlled by a bioresponsive, IL-4 releasing drug delivery system, covalently attached to the supply compartment and releasing this M2 skewing cytokine in response to upregulated collagenase activity. The plans build off our extensive preliminary data and previous publication demonstrating functional bone-like tissue engineering, the genetic engineering of cytokine mutants with an integrated pyrrolysine analogue (propargyl pyrrolysine, plk) for site directed chemistry (including plk-IL-4), an array of more than 200 collagenase sensitive cleavable linker sequences and successful binding of these bioresponsive drug delivery systems to SF as a prerequisite for controlled, bioresponsive macrophage skewing, and relevant animal model systems for critical size bone defects.

• DFG Programme: Research Grants
• International Connection: China
• Cooperation Partner: Professor Hongwei Ouyang, Ph.D.