Biomechanics-on-a-chip: Combining a biphasic multicellular organoid and a complex microphysiological system to unravel mechanotransduction.

• Applicants: Dr. Anne Bernhardt; Dr.-Ing. Frank Schulze
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Microsystems
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575331493

The process of ageing leads to a functional deficit in bone, which manifests as a decrease in bone mass, density, and quality, thereby increasing overall frailty in humans. In bone, osteoblasts (OBs) and osteocytes (OCYs) play a key role in tissue remodeling and formation. OCYs form a highly interconnected dendritic network, thus enabling these cells to sense mechanical forces throughout bone while simultaneously being able to stimulate the local activity of bone-forming OBs. With increasing age, the anabolic effect that mechanical loading has on bone tissue diminishes, leading to a general deterioration in the mechanical properties of the tissue. In this context, it remains unclear whether the reduced sensitivity to mechanical loading in older individuals is the result of a general loss of function and viability of OBs and OCYs, or rather caused by specific changes in the OCY network and subsequent alterations in OCY-OB crosstalk. Most data on mechanotransduction has been obtained from animal models, particularly rodents. While these models are of great importance for understanding fundamental processes in bone, physiological and biological differences limit the direct translation of results to humans. Furthermore, cellular models used to investigate biomechanical signal transduction often rely on immortalized animal cell lines, whereas primary human cells are rarely used for in vitro experiments.As part of the proposed project, primary human OBs will be utilized and further differentiated into OCYs to enable co-culture of both cell types in a 3D model. For this purpose, a biphasic organoid will be generated, consisting of both cell types in separate compartments. To allow for biomechanical investigations, these biphasic organoids will be cultured under standardized cell culture conditions and in a complex microphysiological system (MPS). This MPS has been specifically developed for the cultivation of bone organoids under defined oxygen saturation and mechanical loading. It is planned to create organoids with cells from both elderly and young donors. Through direct comparison of cellular crosstalk under mechanical loading, new insights into the aging process of bone will be gained. This knowledge is intended to pave the way for exploring new treatments for age-related bone loss, which could significantly improve quality for elderly people.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr.-Ing. Mark Vehse