Can pretreating stem cells with electrical stimulation prior to their use in bone tissue engineering improve outcomes?

• Applicant: Professor Dirk Henrich, Ph.D., since 3/2022
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429476343

Delayed and non-healing large bone defects present a major challenge for the patients who suffer with them, the surgeons who treat them, and the healthcare systems burdened with their high costs. Several treatments are available, of which autologous bone grafts are considered to be the gold standard. The success of autologous bone grafts lies in the fact that bone missing from a defect is replaced with autologous bone forming cells, signaling growth factors, and 3D structural scaffolding, which reestablishes an ideal environment for healing. Bone Tissue Engineering (BTE) treatments replicate these benefits, with the added advantage of being able to manipulate the type and/or activity of the implanted cells, growth factors, and scaffolds to further optimize healing. While the use of electrical stimulation (EStim) for treating bone fractures is not new, only recently we have begun to understand the mechanisms by which EStim promotes bone healing. Recent in vitro studies suggest that EStim exerts its pro-healing effects by enhancing cell migration, proliferation, alignment, differentiation and attachment to scaffolds. If these cell functions could be regulated, they could be used to significantly improve BTE treatment outcomes. In previous in vitro experiments we exposed MSC alone and MSC + scaffold (to simulate BTE treatments) to EStim 1h/day and observed significant increases in osteogenic differentiation, calcium deposition, and expression of osteogenic gene markers. Remarkably, and particularly relevant to the work proposed here, we also found that when EStim treatment of MSC was stopped after 7 days, the improved osteogenic effects persisted long after discontinuing EStim exposure. This finding suggests that EStim may activate a switch that causes sustained, long-lasting positive osteogenic activity in these cells. A major problem associated with treating bone fractures with direct current EStim is the need to surgically implant, monitor, and explant the EStim hardware used to administer this treatment. The goal of the project proposed here is to eliminate these drawbacks and still benefit from the positive osteogenic effects of EStim on bone healing. We plan to achieve this goal in 2 specific aims: 1) In in vivo experiments, we will determine if treating rat femur large bone defects with 2D and 3D EStim-pretreated constructs improves the rate and quality of bone healing, 2) in in vitro experiments, we will investigate the underlying mechanisms by which EStim influences cell behavior. Achieving these aims could lead to discoveries to improve BTE treatment outcomes, and in doing so help this exciting new treatment approach reach its full therapeutic potential.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. John Barker
• Ehemalige Antragstellerin: Karla Mychellyne Costa Oliveira, Ph.D., until 2/2022